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Putting female mosquitoes on human diet drugs could reduce spread of disease

Source: Cell Press
Date: 02/07/2019
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Unlike humans, who usually get hungry again only a few hours after eating, a female mosquito that has fed on human blood will lose her appetite for several days. Because movement of female mosquitoes from human to human–male mosquitoes do not consume blood–is the means by which mosquito-borne infections are passed along, researchers have theorized that reducing the frequency with which female mosquitoes feed is one way to lessen the spread of disease.

In a study publishing February 7 in the journal Cell, researchers report that they have identified drugs that can reduce mosquito hunger for blood. These compounds act on the hormone pathways that signal to a female mosquito that she’s full.

“We’re starting to run out of ideas for ways to deal with insects that spread diseases, and this is a completely new way to think about insect control,” says senior author Leslie Vosshall, a Howard Hughes Medical Institute investigator and head of the Laboratory of Neurogenetics and Behavior at Rockefeller University. “Insecticides are failing because of resistance, we haven’t come up with a way to make better repellents, and we don’t yet have vaccines that work well enough against most mosquito-borne diseases to be useful.”

The new research used Aedes aegypti mosquitoes, which spread pathogenic viruses including yellow fever, dengue, Zika, and chikungunya. Female Ae. aegypti feed on human blood to nourish their growing eggs. Because a female Ae. aegypti mosquito has several broods over the course of her lifetime, she requires multiple meals. This cycling behavior results in a number of opportunities to pass an infectious virus from one human to another.

But after consuming a meal that doubles her body weight, the female mosquito loses the drive to eat again for at least four days. Vosshall’s lab hypothesized that certain neuropeptide hormones were responsible for a mosquito’s attraction to humans and that feeding turned these pathways off. “We know these pathways are important in hunger in humans. Because they are evolutionarily conserved, we made the decision to use human diet drugs to see if they would suppress the appetite of the mosquitoes,” she explains. “Finding that the pathways work the same way in the mosquitoes gave us the confidence to move ahead with this research.”

Her lab identified a receptor called neuropeptide Y-like receptor 7 (NPYLR7) as the one that signals to the female mosquito whether or not she’s hungry. They then performed high-throughput screening in tissue culture cells of more than 265,000 compounds to determine which ones would activate the NPYLR7 receptor.

Once they identified the best candidates, they tested 24 of them, in the mosquitoes and found that compound 18 worked best. The drug was capable of inhibiting biting and feeding behaviors when the mosquitoes were introduced to the scent of a human or a source of warm blood. “When they’re hungry, these mosquitoes are super motivated. They fly toward the scent of a human the same way that we might approach a chocolate cake,” Vosshall says. “But after they were given the drug, they lost interest.”

More work must be done before a compound can be developed for mosquito control. Researchers need to further understand the basic biology of the receptor and how it might best be exploited. In addition, future studies would need to focus on how to best get the drugs to the mosquitoes. One idea is a feeder that would attract the females to come and drink the drug rather than drinking blood.

Vosshall notes that if the techniques prove effective, they are likely to work with other kinds of mosquitoes, such as those that spread malaria, as well as other arthropods that feed on human blood, including the ticks that spread Lyme disease.

“Another benefit to this approach is that the effects of the drug are not permanent,” she concludes. “It reduces the appetite for a few days, which will also naturally reduce reproduction, but it doesn’t attempt to eradicate mosquitoes, an approach that could have many other unintended consequences.”

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This research was supported an Advanced Grant from the Robertson Therapeutic Development Fund, the National Institutes of Health, a Rockefeller University Women & Science Fellowship, an APS Postdoctoral Fellowship in Biological Science from the American Philosophical Society, and the Howard Hughes Medical Institute.

Cell, Duvall et al: “Novel small molecule agonists of an Aedes aegypti neuropeptide Y receptor block mosquito biting behavior.” https://www.cell.com/cell/fulltext/S0092-8674(18)31587-3

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Electrical signals kick off flatworm regeneration

Source: Cell Press
Date: 03/05/2019
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Unlike most multicellular animals, planarian flatworms can regrow all their body parts after they are removed. This makes them a good model for studying the phenomenon of tissue regeneration. They are also useful for exploring fundamental questions in developmental biology about what underlies large-scale anatomical patterning.

In a study publishing March 5 in Biophysical Journal, scientists report that electrical activity is the first known step in the tissue-regeneration process, starting before the earliest known genetic machinery kicks in and setting off the downstream activities of gene transcription needed to construct new heads or tails.

“It’s incredibly important to understand how cells make decisions about what to build,” says senior author Michael Levin (@drmichaellevin), director of the Allen Discovery Center at Tufts University. “We’ve found that endogenous electrical signals enable cells to communicate and make decisions about their position and overall organ structure, so they know which genes to turn on.”

The species used in the study was Dugesia japonica. When parts of this flatworm are removed, the remaining tissues regrow the missing pieces at the correct ends–whether a head or a tail. Previous studies had shown that about six hours after amputation, the first genes associated with regrowing a missing part are turned on. But until now, it wasn’t known what happened before that or what mechanisms control which genes get turned on.

In the current experiments, led by Fallon Durant, who was a graduate student at the time, the heads and tails of the flatworms were removed. The researchers used voltage-sensitive fluorescent dyes that were able to indicate the various electrical potentials of the different regions. “You can literally see the electrical activity in the tissue,” Levin says. “Within a few hours of when this activity is seen, we can start to measure changes in gene expression.”

To show that a specific voltage pattern was responsible for turning on correct genes for each wound site, the team altered the resting potentials of cells at the different ends of the worms and observed the effects. By inducing ion flows that set each wound site to head- or tail-specific voltage patterns, they can create flatworms with two heads and no tail. They also studied the relationship between this electrical signal and the well-known Wnt protein signaling pathway, functioning downstream of the voltage-mediated decision machinery.

“Most of the people working on this problem study genetic and biochemical signals like transcription factors or growth factors,” Levin says. “We’ve decided to focus on electrical signals, which are a very important part of cell-to-cell communication.” He compares the electrical signals his group studies to those that occur in the brain. “A stimulus comes in and an electrical event triggers biochemical second-messenger events in the cells and downstream activity of the electrical network, such as decision making or forming a memory,” he notes. “This electrical system is super ancient and very highly conserved.”

Future research will focus on breaking down these signals in much more detail. For example, researchers would like to know how regenerated tissues make decisions about the size, shape, and scale of the new parts that they grow and how the bioelectric circuits store changes in body patterning, as is seen in two-headed worms that continue to make two-headed animals in subsequent rounds of regeneration.

“With perhaps the exception of infectious disease, the majority of problems in health and biomedicine hinge on understanding how cells get together to build a specific organ or other structure,” Levin concludes. “If we can figure out how to manipulate these processes, we can start to develop ways to correct birth defects and address everything from traumatic injury to degenerative diseases, aging, and cancer.”

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This research was funded by an Allen Discovery Center Award from the Paul G. Allen Frontiers Group, the G. Harold and Leila Y. Foundation, the Templeton Foundation, and the National Science Foundation.

Biophysical Journal, Durant et al.: “The role of early bioelectric signals in the regeneration of planarian anterior/posterior polarity” https://www.cell.com/biophysj/fulltext/S0006-3495(19)30065-7

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Using more-specific ‘genetic scissors’ may avoid problems associated with gene editing

Source: Cell Press
Date: 03/21/2019
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Recent studies have suggested a potential barrier to making CRISPR gene-editing treatments a viable option for inherited blood-related disorders such as sickle cell anemia, thalassemia, and primary immunodeficiency syndromes. Stem cells may respond to having their genes edited by shutting down–and trying to get around this roadblock could increase the risk of cancer.

Now, a study from researchers in Italy has suggested that there could be a way to bypass these complications. The team found that using more-precise gene-editing technology that induces fewer breaks in DNA may keep stem cells’ natural damage-response pathways under control. The findings are published March 21 in the journal Cell Stem Cell.

“Genome editing is a very powerful strategy for precise genetic engineering of stem cells, but it requires a complex procedure,” says co-senior author Pietro Genovese, a scientist at the San Raffaele Telethon Institute for Gene Therapy in Milan. “Despite its tremendous therapeutic potential and the continuous advances in perfecting gene-editing platforms, the functional consequences of the editing process have yet to be fully elucidated.”

One of the barriers to successful genome editing turns out to be p53, a protein that’s often called “the guardian of the genome” due to its role in conserving the stability of DNA and preventing mutations. When CRISPR edits genes, it cuts both strands of DNA at particular locations. But these double-strand breaks can signal to p53 that something is wrong. The protein then kicks into action and prevents the cells from proliferating. This is the opposite of what’s desired when cells are being used as a potential therapy. Yet permanently shutting down p53 to prevent this defense mechanism can lead to the formation of tumors; defective p53 has been implicated in about half of all cancers.

The team in Milan found a way around this unwanted consequence. Gene editing uses nucleases as “genetic scissors” to induce DNA breaks, followed by an adeno-associated viral vector that delivers the corrective sequence. But when these scissors are not specific enough, they may cut DNA in many additional places. The investigators used a combination of highly specific nucleases and vectors to introduce only the desired break in the DNA of hematopoietic stem/progenitor cells (HSPCs).

“We showed that the impact of gene editing on HSPCs highly depends on the precision of the designer nuclease used,” says Luigi Naldini, another study co-senior author and director of the San Raffaele Telethon Institute for Gene Therapy. “If the nucleases are not highly specific, and thus cut the DNA not only at the intended target but also at a few additional off-target sites, we do see robust and prolonged p53 response leading to detrimental effects up to irreversible cell arrest.

“On the other hand,” he adds, “if the nuclease is highly specific–and we use highly purified reagents and optimized protocols–we only see a transient effect on cell proliferation. This appears to be fully reversible and compatible with maintenance of the important biological properties of the hematopoietic stem cells.”

“Earlier studies pointed to the theoretical risk of selecting for p53-inactivating mutations upon editing, thus highlighting a possible tumorigenic risk associated with gene-editing procedures in a way that could jeopardize its therapeutic potential,” says Raffaella Di Micco, the study’s third co-senior author, who heads a lab at the San Raffaele Telethon Institute for Gene Therapy. “Our work shows that HSPCs tolerate one or a few DNA breaks well, with only transient p53 activation and a limited impact on their functionality (mainly manifesting of delayed proliferation). This cellular response is slightly more prolonged when highly specific ‘genetic scissors’ are used in combination with adeno-associated viral vectors delivering the corrective DNA sequence. However, if we transiently inactivate the p53 response during gene editing we may counteract this effect and improve the yield of edited cells, without indication of increased mutations or genome instability.”

“The other major challenge of gene editing in HSPCs has been the relatively low efficiency of homologous recombination in HSPCs, which is required for introducing the corrective sequence delivered by the repair template,” Naldini concludes. “This hurdle has now been substantially alleviated by new techniques described in our and other recent papers.”

The researchers say this work provides molecular evidence for the feasibility and efficacy of genetic engineering in HSPCs. This gives them confidence that the technology will be successfully translated to human trials.

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This work was supported by grants from Telethon, the Italian Ministry of Health, and the Human Frontier Science Program (HFSP) Long- Term/Cross-Disciplinary Fellowship. It was also supported by an ATIP-Avenir program (Inserm/CNRS, France), the French Cancer Research Association (ARC foundation, France), a Pilot and Seed Grant from Ospedale San Raffaele, and a FIRC-AIRC fellowship for Italy.

Luigi Naldini has received funding from Editas Medicine for a collaborative gene editing project distinct from the work reported here. He is also member of the scientific advisory board of Sangamo Therapeutics. Luigi Naldini and Pietro Genovese are inventors on patents concerning application of gene editing in HSPC gene therapy owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation, including a patent application on the use of p53 inhibitor in gene editing recently filed by several of the authors on this study.

Cell Stem Cell, Schiroli et al.: “Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient p53-Mediated DNA Damage Response” https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30071-2

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Mouse study examines the underpinnings of hallucinations

Source: Cell Press
Date: 03/26/2019
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Hallucinations result in dramatic disruptions in perception and cognition, but the changes in brain activity that underlie such alterations are not well understood. In a study publishing March 26 in the journal Cell Reports, researchers looked at how a hallucinogenic drug impacts the brains of mice at the level of individual neurons. They found that visual hallucinations may be triggered by a reduction in signaling within the visual cortex, rather than an increase, and by altered timing of when the neurons fire.

In addition to helping us understand how hallucinogens affect brain function, the findings also have implications for figuring out the neurological underpinnings in disorders like schizophrenia that are characterized by hallucinations.

“You might expect visual hallucinations would result from neurons in the brain firing like crazy, or by mismatched signals. We were surprised to find that a hallucinogenic drug instead led to a reduction of activity in the visual cortex,” says senior author Cris Niell, an associate professor and member of the Institute of Neuroscience at the University of Oregon.

“In the context of visual processing, though, it made sense,” he adds. “Understanding what’s happening in the world is a balance of taking in information and your interpretation of that information. If you’re putting less weight on what’s going on around you but then overinterpreting it, that could lead to hallucinations.” One example of this is the vivid images that are often seen in dreams, despite no visual signals coming in to the brain; another example is the hallucinations experienced after spending long periods of time in the dark.

“We’re interested in understanding how we create representations of the world using vision,” he says. “In many areas of biology, one of the best ways to study a process is to observe what happens when it’s perturbed.” The researchers, including graduate student Angie Michaiel and postdoctoral fellow Phil Parker, decided that inducing hallucinations would be a good way to investigate disrupted visual signals in the brain.

The drug given to the mice in the study is called DOI (4-iodo-2,5-dimethoxyphenylisopropylamine) and is often used in animal studies. Like other hallucinogenic drugs, including LSD and psilocybin, it acts on serotonin 2A receptors. But unlike those other drugs, it’s not regulated by the Drug Enforcement Agency as a Schedule 1 drug, making it more accessible for research purposes.

After being given the drug, the mice were shown images on a screen. The researchers used calcium imaging and single-unit electrophysiology to monitor the responses in their brains and look at which neurons were affected by both the visual stimulation and the drug. They observed that there was an alteration in timing in the neurons, which was accompanied by a reduction in signaling. The fact that the mice were awake was significant: Much of the previous research on the effects of activating serotonin 2A receptors in the brain has been done in animals that were anesthetized.

The researchers were also able to confirm that the overall signals being sent, and organization of brain activity across the visual cortex, was similar to what is seen in the absence of the drug. This suggests the visual information being conveyed to the brain is not changed–it is just reduced in amplitude and altered in timing. These types of measurements are not accessible in data obtained from neuroimaging studies in humans.

There are limitations to studying visual hallucinations in animal models because animals can’t directly report what they’re seeing. But research has shown that drugs that cause hallucinations in humans cause reliable movement changes in mice, such as head twitches and unusual paw movements, suggesting that they similarly affect brain function. Future experiments will examine the ability of mice to make visual discriminations, which could potentially reveal whether perception is altered.

“I don’t feel like we’ve necessarily found the smoking gun for the entire underlying cause of hallucinations, but this is likely to be a piece of it,” Niell concludes. “The data we’ve collected will provide a foundation for additional studies going forward. In particular, we plan to use genetic manipulation to study particular parts of this circuit in more detail.” Additionally, because the serotonin 2A receptor is known to play a role in schizophrenia, the investigators say it may be possible to apply these findings toward gaining a better understanding of what’s happening in the brain with that disease.

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This work was supported by the National Institutes of Health.

Cell Reports, Michaiel et al.: “A hallucinogenic serotonin-2A receptor agonist reduces visual response gain and alters temporal dynamics in mouse V1” https://www.cell.com/cell-reports/fulltext/S2211-1247(19)30290-6

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In mice, single population of stem cells contributes to lifelong hippocampal neurogenesis

Source: Cell Press
Date: 03/28/2019
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Scientists once thought that mammals entered adulthood with all of the neurons they would ever have, but studies from the 60s found that new neurons are generated in certain parts of the adult brain and pioneering studies from the 90s helped identify their origins and function. In the latest update, a team of researchers has shown in mice that a single lineage of neural progenitors contributes to embryonic, early postnatal, and adult neurogenesis in the hippocampus, and that these cells are continuously generated throughout a lifetime. The study appears March 28 in the journal Cell.

“Conceptually, this suggests that our brains have the capacity for continuous improvement, adaptation, and incorporation of new cells into the circuitry,” says senior author Hongjun Song of the Perelman School of Medicine at the University of Pennsylvania. “This turns out to be very important, because the hippocampus is well known to be important for learning, memory, and mood regulation.”

Neurogenesis was originally believed to have two phases: the developmental phase, which occurred mostly in embryos and immediately after birth and in which neurons are generated from a stem cell that build up circuitries of the full nervous system. Adult neurogenesis was thought to originate from a specialized population of neural stem cells that were “set aside” and distinct from the precursors generating neurons during embryogenesis. But it turns out it’s not so straightforward.

In the current study, the researchers labelled precursor neural stem cells in mice at a very early stage of brain development. They then followed the lineage of cells throughout development and into adulthood. Their findings revealed that new neural stem cells with the precursor cells’ label were continuously generated throughout the animals’ lifetimes.

RNA-seq and ATAC-seq analyses were used to confirm that all the cells in the lineage had a common molecular signature and the same developmental dynamics.

“Earlier studies have suggested that specific parts of the brain, such as the olfactory bulb and the hippocampus, can generate neurons,” Song says. “Until this study, it wasn’t clear how this happens. We’ve shown for the first time in a mammalian brain that development is ongoing from the beginning, and that this one process happens over a continuum that lasts a lifetime.”

The prevalence of adult neurogenesis in humans and primates is an area of active discussion in the field and more research is needed to determine whether the process of stem cell generation observed in the mouse pertains to other mammals too. The investigators plan to study the processes of neurogenesis in more detail, to look for ways to potentially increase or preserve it, as well as to determine how it’s regulated at the molecular level.

“This paper has implications for understanding how the brain maintains a ‘young’ state for learning and memory,” says co-senior author Guo-li Ming, also of the Perelman School of Medicine. Additionally, “if we could harness this capacity and this mechanism, we may be able to repair and regenerate parts of the brain,” she concludes.

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This research was supported by the National Institutes of Health, an EMBO postdoctoral fellowship, and the Swedish Research Council.

Cell, Berg et al.: “A Common Embryonic Origin of Stem Cells for Continuous Developmental and Adult Neurogenesis” https://www.cell.com/cell/fulltext/S0092-8674(19)30159-X

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Two studies explore whether time of day can affect the body’s response to exercise

Source: Cell Press
Date: 04/18/2019
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Two papers appearing April 18 in the journal Cell Metabolism confirm that the circadian clock is an important factor in how the body responds to physical exertion. The studies focused on different components of exercise, thereby complementing each other. Based on this work alone, it’s too early to say when the best time is for you to go for a jog. But at least in the lab, exercise in the evening seems to be more productive, although human lifestyles are much more complicated and so this area of research is only just beginning.

“It’s quite well known that almost every aspect of our physiology and metabolism is dictated by the circadian clock,” says Gad Asher of the Department of Biomolecular Sciences at the Weizmann Institute of Science, who is senior author of one of the studies. “This is true not only in humans but in every organism that is sensitive to light. We decided to ask whether there is a connection between the time of day and exercise performance.”

“Circadian rhythms dominate everything we do,” adds Paolo Sassone-Corsi of the Center for Epigenetics and Metabolism at the University of California, Irvine, who is senior author of the other paper. “Previous studies from our lab have suggested that at least 50% of our metabolism is circadian, and 50% of the metabolites in our body oscillate based on the circadian cycle. It makes sense that exercise would be one of the things that’s impacted.”

Both research teams looked at the association between time of day and exercise performance primarily in mice. Because mice are nocturnal, one thing they had to do was translate mouse timing to human timing, by distinguishing between the active phase and resting phase of the mice rather than using numbers on the clock.

Asher’s group started by putting mice in treadmills at different times of day within their active phase. They examined the exercise capacity of mice upon different exercise intensities and regimens and found that overall exercise performance is substantially better (about 50% on average and more in some protocols) in the “mouse evening” (toward the end of their active time) compared to the morning hours. These daily differences were diminished in mice that had mutant clocks–supporting a potential role of the clock in the observed variance in exercise performance.

To identify a potential determinant of daily variance in exercise performance, they applied high-throughput transcriptomics and metabolomics on muscle tissue. The researchers found that in response to exercise in the “mouse evening,” there were higher levels of a metabolite called ZMP (5-aminoimidazole-4-carboxamide ribonucleotide). ZMP is known to activate metabolic pathways that are related to glycolysis and fatty acid oxidation through activation of AMPK, which is a master cellular metabolic regulator. Therefore, it is likely to contribute to the increased exercise capacity in the evening. “Interestingly, ZMP is an endogenous analog of AICAR [aminoimidazole carboxamide riboside], a compound that some athletes use for doping,” Asher says.

The researchers also studied 12 humans and found similar effects. Overall, the people in the study had lower oxygen consumption while exercising in the evening compared with the morning; this translated to better exercise efficiency.

Sassone-Corsi’s team also put mice on treadmills, but they had a different approach. Using high-throughput transcriptomics and metabolomics to look at a wide range of possible factors, they characterized the changes in the mice’s muscle tissue that occur in response to exercise. This allowed them to look at processes like glycolysis (which contributes to sugar metabolism and energy production) and lipid oxidation (fat burning).

They found that a protein called hypoxia-inducible factor 1-alpha (HIF-1α) plays an important role and that it is activated by exercise in different ways depending on the time of day. HIF-1α is a transcription factor that is known to stimulate certain genes based on oxygen levels in tissue. “It makes sense that HIF-1α would be important here, but until now we didn’t know that its levels fluctuate based on the time of day,” Sassone-Corsi says. “This is a new finding.”

Based on the work from the UC Irvine team, exercise seemed to have the most beneficial impact on the metabolism at the beginning of the active phase phase (equivalent to late morning in humans) compared with the resting phase (evening).

The researchers note that even though circadian clocks have been conserved throughout evolution, translating the findings to humans is not so straightforward. One reason is that humans have more variation in their chronotypes than mice living in a lab. “You may be a morning person, or you may be a night person, and those things have to be taken into account,” Sassone-Corsi says.

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Cell Metabolism, Ezagouri, Zwighaft, and Sobel et al.: “Physiological and Molecular Dissection of Daily Variance in Exercise Capacity” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30141-X DOI: 10.1016/j.cmet.2019.03.012

This study was supported by the European Research Council and an EMBO Young Investigator Award. It was also supported by Fonds de Dotation AGIR pour les Maladies Chroniques and a fellowship from the Placid Nicod Foundation.

Cell Metabolism, Sato et al.: “Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30183-4 DOI: 10.1016/j.cmet.2019.03.013

This study was supported by the Novo Nordisk Foundation, the Swedish Diabetes Foundation, the Swedish Research Council, the National Institutes of Health, INSERM, and the Della Martin Foundation.

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Pole-to-pole study of ocean life identifies nearly 200,000 marine viruses

Source: Cell Press
Date: 04/25/2019
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An international team has conducted the first-ever global survey of the ecological diversity of viruses in the oceans during expeditions aboard a single sailboat, the Tara. They identified nearly 200,000 marine viral species, which vastly exceeds the 15,000 known from prior ocean surveys of these waters and the approximately 2,000 genomes available from cultured viruses of microbes. Their findings, appearing April 25 in the journal Cell, have implications for understanding issues ranging from evolution to climate change, because they help create a new picture of our planet and how it may be impacted by interactions among organisms.

“Viruses are these tiny things that you can’t even see, but because they’re present in such huge numbers, they really matter,” says senior author Matthew Sullivan (@Lab_Sullivan), a microbiologist at the Ohio State University. “We’ve developed a distribution map that is foundational for anyone who wants to study how viruses manipulate the ecosystem. There were many things that surprised us about our findings.”

Among the surprises was the existence of these nearly 200,000 marine viral species. Additionally, meta-community analysis showed that the viruses were organized into five distinct ecological zones throughout the entire ocean, which was unexpected given the fluid nature of the oceans and the complexity of many of the marine regions. Also, despite the paradigm from larger organisms that species diversity is highest near the equator and lowest near the poles, the researchers collected an extensive number of samples in the Arctic compared to previous studies of ocean life and found a biodiversity hotspot in the Arctic Ocean.

The samples were collected between 2009 and 2013 on the Tara as part of the Tara Oceans effort. Begun in 2006, the Tara project aims to conduct unique and innovative ocean science with the goal of predicting and better anticipating the impacts of climate change. In the current effort, a rotating team of scientists spent time on the boat collecting ocean water samples from different depths across many geographical regions. After being collected, the samples for this study were filtered and shipped back to about a dozen different labs for analysis.

The investigators studied not only the water samples for viruses, but also other microbes and other living creatures. “We filtered the samples to analyze organisms ranging in size from viruses to fish eggs,” Sullivan says. He adds that papers reporting some of the other microbial components from the samples are forthcoming.

Another noteworthy aspect of the project was the extensive number of samples collected in the Arctic, a highlight that has not been part of earlier studies of ocean life.

This research has significant implications for understanding how ocean microorganisms affect the earth’s atmosphere. “In the last 20 years or so, we’ve learned that half of the oxygen that we breathe comes from marine organisms,” Sullivan notes. “Additionally, the oceans soak up half of the carbon dioxide from the atmosphere.”

“Because of complex chemistry, increased levels of carbon dioxide at the surface acidify the oceans,” Sullivan adds. “However, if carbon dioxide instead is converted to organic carbon and biomass, then it can become particulate and sink into the deep oceans. That’s a good result for helping mitigate human-induced climate change–and we’re learning that viruses can help facilitate this sinking. Having a new map of where these viruses are located can help us understand this ocean carbon “pump” and, more broadly, biogeochemistry that impacts the planet.”

The investigators say that having a more complete picture of marine viral distribution and abundance will help them to determine which viruses they should be focusing on for further studies. Additionally, the maps based on this research establish a baseline for other collection efforts going forward, which can help to answer questions about how levels of microorganisms change over time, in response to both seasonal variation and climate change.

“Previous ocean ecosystem models have commonly ignored microbes, and rarely included viruses, but we now know they are a vital component to include,” Sullivan concludes.

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The study’s two first authors were Ohio State graduate students Ann C. Gregory and Ahmed Zayed. This research was made possible by the scientists and crew who sampled aboard the Tara, as well as the leadership of the Tara Expeditions Foundation. Funding was provided by the Gordon and Betty Moore Foundation, the National Science Foundation, Oceanomics, France Genomique, ETH (the Swiss Federal Institute of Technology), the Helmut Horten Foundation, a Netherlands Organization for Scientific Research Vidi grant, and a National Institutes of Health training grant fellowship.

Cell, Gregory et al: “Marine viral macro- and micro-diversity from pole to pole.” https://www.cell.com/cell/fulltext/S0092-8674(19)30341-1

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Examining ethical issues surrounding wearable brain devices marketed to consumers

Source: Cell Press
Date: 05/22/2019
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Wearable brain devices are now being marketed directly to consumers and often claim to confer benefits like boosting memory and modulating symptoms of depression. But despite the size of this market, little is known about the validity of these claims and, substantiated or not, the related ethical consequences or repercussions.

In a perspective being published in the journal Neuron on May 22, a team of neuroethicists looked at the range of products being sold online and questioned the claims made by companies about these products. They identified 41 devices for sale, including 22 recording devices and 19 stimulating devices. The goal of the project was to look at issues of transparency, rights, and responsibility in the way these products are marketed and sold.

“When it comes to biotechnology, and in particular brain technology, there is a heightened level of responsibility around ethical innovation,” says senior author Judy Illes, a professor of Neurology and Canada Research Chair in Neuroethics at the University of British Columbia (@NeuroethicsUBC). “The great news is that it doesn’t cost a lot of money to innovate ethically: it just takes some more thought, good messaging, and consideration of potential consequences. There are many experts who are poised to help this industry in a practical, solution-oriented way. It’s worth it for companies to take the time to do it right.”

The authors established four general categories for the claims about wearable brain devices:

  • Wellness: benefits like stress reduction, improved sleep, and weight loss
  • Enhancement: including improved cognition and productivity and greater physical performance
  • Practical applications: uses like research and enhanced worker safety
  • Health: improvement of conditions such as those affecting behavior and attention, as well as certain neurodegenerative diseases

Despite wide-ranging claims, there have been few studies evaluating the scientific validity of any of them. The authors didn’t seek to evaluate the products’ effectiveness in this review. Instead, they looked at how manufacturers could communicate the potential outcomes from using these devices–both positive and negative–in a more ethically responsible way.

The neuroscience wearables market has parallels to other direct-to-consumer medical products. This includes herbs and supplements, home genetic testing kits, so-called wellness CT scans, and “keepsake” 3D ultrasounds offered to pregnant women. By marketing them for wellness or recreation rather than health, companies that sell these products and services are able to avoid regulatory oversight from agencies such as the Food and Drug Administration.

“We have concerns, however, that people could turn to these devices rather than seeking medical help when they might actually need it,” Illes notes. “They may also choose these devices over conventional medical treatments that they have been offered. There are a lot of potential effects that we don’t know much about.”

Symptoms and side effects that could result from use of these products include redness or other irritation where the devices contact the skin, headaches, pain, tingling, and nausea. Some of the products mention the possibility of side effects in their packaging, but there haven’t been any studies looking at how common or serious the effects may be.

The researchers note that warning labels advising consumers about risk are largely lacking. “I would consider this an important, responsible message to consumers, but as far as I know, few of these products have it,” Illes says.

Illes and her team believe that because some of these products are marketed for children, who may be particularly vulnerable to their effects on the brain, extra caution is needed. “Their bodies and brains are still developing,” she says. “What are the claims for these products and how do we manage and appreciate them both for their potential benefits and possible risks?” Additional caution may also be needed for use of neuroscience wearables in the elderly, another population that may have a higher risk of potential harm.

There are also issues related to neuroscience wearable products that record brain activity. “How are these data used, and who has access to them?” Illes asks. “These are things we don’t know. We should be asking these questions.”

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This work was supported by Technical Safety BC, an independent, self-funded organization mandated to oversee the safe installation and operation of technical systems and equipment.

Neuron, Coates McCall et al.: “Owning Ethical Innovation: Claims about Commercial Wearable Brain Technologies” https://www.cell.com/neuron/fulltext/S0896-6273(19)30289-2

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Controlled study links processed food to increased calorie consumption

Source: Cell Press
Date: 05/16/2019
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Experts have long suspected that increased consumption of processed foods over the past 50 years has been a primary driver of the obesity epidemic. But because studying dietary habits is complicated, it’s been difficult to make a direct connection.

On May 16 in the journal Cell Metabolism, researchers report results from the first randomized, controlled trial that directly compared differences in calorie consumption and weight gain between an ultra-processed and an unprocessed diet. The team found that even when the two diets were matched for the amount of presented carbohydrates, fat, sugar, salt, and calories, people consumed more food and gained weight on an ultra-processed diet.

“I was surprised by the findings from this study, because I thought that if we matched the two diets for components like sugars, fat, carbohydrates, protein, and sodium, there wouldn’t be anything magical about the ultra-processed food that would cause people to eat more,” says lead author Kevin Hall, a section chief in the Laboratory of Biological Modeling at the National Institute of Diabetes and Digestive and Kidney Diseases within the National Institutes of Health. “But we found that, in fact, people ate many more calories on the ultra-processed diet, and this caused them to gain weight and body fat.”

The study enrolled 20 healthy volunteers who were admitted to the NIH’s Metabolic Clinical Research Unit for a month. Each participant was given either an ultra-processed diet or an unprocessed diet for two weeks, and then switched. The participants were given three meals a day and had access to bottled water and either ultra-processed or unprocessed snacks throughout the day. They were told they could eat as much as they wanted, and the quantities they consumed were measured.

The researchers used the NOVA food classification system, which categorizes foods according to the extent and purpose of processing, to develop the two diets. For example, one ultra-processed breakfast consisted of Honey Nut Cheerios, whole milk with added fiber, a packaged blueberry muffin, and margarine; an unprocessed one was a parfait made with plain Greek yogurt, strawberries, bananas, walnuts, salt, and olive oil and apple slices with fresh-squeezed lemon. Participants reported that both diets tasted good and were satisfying, eliminating food preference as a factor.

During the two weeks that they were given ultra-processed food, the people in the study consumed an average of 508 calories more per day, compared with the days they got unprocessed food. Two weeks on the ultra-processed diet resulted in an average weight gain of two pounds, compared with an average weight loss of two pounds for the two weeks on the unprocessed diet. The volunteers gained body fat on the ultra-processed diet and lost it on the unprocessed diet.

Metabolic testing revealed that when participants ate the ultra-processed diet, they expended more energy than when they ate the unprocessed diet, but not enough to make up for the increased number of calories they consumed. Because the participants were healthy and the testing period lasted only a month, the investigators didn’t see significant differences in other measures of health, such as liver fat or blood glucose.

The researchers have several hypotheses for why the people on the ultra-processed diet consumed more food.

When people were on the ultra-processed diet, they ate faster. “There may be something about the textural or sensory properties of the food that made them eat more quickly,” Hall says. “If you’re eating very quickly, perhaps you’re not giving your gastrointestinal tract enough time to signal to your brain that you’re full. When this happens, you might easily overeat.”

Another hypothesis is the role of solid foods versus beverages. To balance the dietary fiber and match the calorie density of the overall diets, drinks were added to the ultra-processed meals, such as juice and lemonade, that had added fiber. But some researchers believe that beverages don’t contribute to satiety the same way that solid foods do. So, the higher calorie density of the solid foods in the ultra-processed diet could have led people to increase their overall calorie intake.

A third factor could be that although the diets were matched as closely as possible, the unprocessed diet contained slightly more protein, about 15.6% of calories versus 14% for the ultra-processed diet. “It could be that people ate more because they were trying to reach certain protein targets,” Hall says.

Future studies will try to account for these factors and explore the possible mechanisms behind the increase in calorie consumption.

The investigators note one important limitation of the study: because all the food was prepared for the participants, it didn’t take into account how convenient they were to make or how much they cost.

“We know there are a lot of factors that contribute to why someone might choose an ultra-processed meal over an unprocessed one,” Hall says. “For people in lower socio-economic brackets especially, we need to be mindful of the skills, equipment, knowledge, and expense needed to create unprocessed meals.”

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This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Cell Metabolism, Hall et al.: “Ultra-processed diets cause excess calorie intake and weight gain: An inpatient randomized controlled trial of ad libitum food intake” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30248-7

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Gut microbes respond differently to foods with similar nutrition labels

Source: Cell Press
Date: 06/12/2019
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Foods that look the same on nutrition labels can have vastly different effects on our microbiomes, report researchers in a paper publishing June 12 in the journal Cell Host & Microbe. The researchers’ observations of participants’ diets and stool samples over the course of 17 days suggested that the correlation between what we eat and what’s happening with our gut microbes might not be as straightforward as we thought. This adds an increased level of complexity to research focused on improving health by manipulating the microbiome.

“Nutrition labels are human-centric,” says senior author Dan Knights (@KnightsDan), of the Department of Computer Science and Engineering and the BioTechnology Institute at the University of Minnesota. “They don’t provide much information about how the microbiome is going to change from day to day or person to person.”

In the study, the investigators enrolled 34 participants to record everything they ate for 17 days. Stool samples were collected daily, and shotgun metagenomic sequencing was performed. This allowed the researchers to see at very high resolution how different people’s microbiomes, as well as the enzymes and metabolic functions that they influence, were changing from day to day in response to what they ate. It provided a resource for analyzing the relationships between dietary changes and how the microbiome changes over time.

“We expected that by doing this dense sampling–where you could see what people were eating every single day and what’s happening to their microbiome–we would be able to correlate dietary nutrients with specific strains of microbes, as well as account for the differences in microbiomes between people,” Knights says. “But what we found were not the strong associations we expected. We had to scratch our heads and come up with a new approach for measuring and comparing the different foods.”

What the researchers observed was a much closer correspondence between changes in the diet and the microbiome when they considered how foods were related to each other rather than only their nutritional content. For example, two different types of leafy greens like spinach and kale may have a similar influence on the microbiome, whereas another type of vegetable like carrots or tomatoes may have a very different impact, even if the conventional nutrient profiles are similar. The researchers developed a tree structure to relate foods to each other and share statistical information across closely related foods.

Two people in the study consumed nothing but Soylent, a meal replacement drink that is popular with people who work in technology. Although it was a very small sample, data from these participants showed variation in the microbiome from day to day, suggesting that a monotonous diet doesn’t necessarily lead to a stable microbiome.

“The microbiome has been linked to a broad range of human conditions, including metabolic disorders, autoimmune diseases, and infections, so there is strong motivation to manipulate the microbiome with diet as a way to influence health,” Knights concludes. “This study suggests that it’s more complicated than just looking at dietary components like fiber and sugar. Much more research is needed before we can understand how the full range of nutrients in food affects how the microbiome responds to what we eat.”

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This work was supported by General Mills Inc.

Cell Host & Microbe, Johnson et al.: “Daily longitudinal sampling reveals personalized diet-microbiome associations.” https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30250-1