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Two studies show that animals’ brain activity ‘syncs’ during social interactions

Source: Cell Press
Date: 06/20/2019
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Two papers publishing June 20 in the journal Cell show that Egyptian fruit bats and mice, respectively, can “sync” brainwaves in social situations. The synchronization of neural activity in the brains of human conversation partners has been shown previously, as a result of one person picking up social cues from the other and modulating their own behavior based on those cues. These studies now suggest that something similar occurs when animals engage in natural social interactions and find that some aspects of the animals’ social behavior can be predicted based on neural observations.

“Animal models are really important for being able to study brain phenomena at levels that we can’t normally access in humans,” says Michael Yartsev of the Department of Bioengineering at the University of California, Berkeley, and senior author of one of the papers. “Because bats are extremely social and naturally live in highly complex social environments, they are a great model for tackling important scientific questions about social behavior and the neural mechanisms underlying it.”

“If you think of the brain like a black box that receives input and gives some kind of output in response, studying social interactions is like trying to understand how the output of one box provides input to another, and how those two boxes work together and create a loop,” says Weizhe Hong of the Departments of Biological Chemistry and Neurobiology at the University of California, Los Angeles, and senior author of the other paper. “Our research in mice allows us to peer inside these black boxes and get a better look at the internal machinery.”

Previous studies showing how neural activity in humans becomes synchronized during social interactions have used technologies like fMRI and EEG, which look at brain activity with relatively coarse spatial and temporal resolutions. These studies found that when two people interact, structures in their brain simultaneously decode and respond to signals from the other person.

Because the new studies looked at neural activity at a level of detail that is difficult to obtain in humans, they could explore the detailed neural mechanism underlying this phenomenon.

The Berkeley team monitored the bats for sessions of about 100 minutes each as they engaged in a wide range of natural social interactions, such as grooming, mating, and fighting. The bats were filmed with high-speed cameras, and their specific behaviors and interactions were carefully characterized.

As this was happening, the scientists were using a technology called wireless electrophysiology to simultaneously record the brain activity in the bats’ frontal cortices across a wide range of neural signals, ranging from brain oscillations to individual neurons and local neural populations. They saw that the brains of different bats became highly correlated and that this correlation was most pronounced in the high-frequency range of brain oscillations. Furthermore, the correlation between the brains of individual bats extended across multiple timescales of social interactions, ranging from seconds to hours. Remarkably, by looking at the level of correlation, they could predict whether the bats would initiate social interactions or not.

The UCLA team took a different tack. They used a device called a miniaturized microendoscope to monitor the brain activities of mice during social situations. These tiny devices, which weigh only two grams, are fitted on the mice and allow the researchers to monitor the activity of hundreds of neurons at the same time in both animals. They saw that mice also exhibit interbrain correlations in natural social interactions where animals freely interact with each other. Moreover, the access to thousands of individual neurons gave them an unprecedented view of both animals’ decision-making processes and revealed that interbrain correlation emerges from different sets of neurons that encode one’s own behavior and behavior of the social partner.

Social interactions are often nested within the context of a dominance hierarchy. By imaging two mice in a competitive social interaction, they discovered that behavior of the dominant animal drives synchrony more strongly than behavior of the subordinate animal. Remarkably, they also found that the level of correlation between two brains predicts how mice will respond to each other’s behavior as well as the dominance relationships that develop between them.

“Natural social interactions are complex,” says Wujie Zhang, a postdoctoral researcher in Yartsev’s lab and first author of the fruit bat paper. “It is important to embrace this complexity in order to understand real-life social interactions at the neural level.”

“We know that social interactions are altered in many mental diseases in human, including autism spectrum disorders and schizophrenia,” says Lyle Kingsbury, a graduate student in Hong’s lab and first author of the mouse paper. “Developing a genetically tractable model system opens up the possibility of exploring how interbrain synchrony is disrupted in people with these conditions and may provide novel information about possible interventions.”

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Cell, Zhang and Yartsev: “Correlated Neural Activity Across the Brains of Socially Interacting Bats.” https://www.cell.com/cell/fulltext/S0092-8674(19)30551-3 DOI: 10.1016/j.cell.2019.05.023

This research was supported by the National Institutes of Health, the New York Stem Cell Foundation, the Packard Fellowship, the Klingenstein-Simons Fellowship, the Pew Charitable Trust, and the Dana Foundation.

Cell, Kingsbury et al: “Correlated Neural Activity and Encoding of Behavior Across Brains of Socially Interacting Animals.” https://www.cell.com/cell/fulltext/S0092-8674(19)30550-1 DOI: 10.1016/j.cell.2019.05.022

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Study examines direct-to-consumer stem cell clinics in 6 Southwestern states

Source: Cell Press
Date: 08/01/2019
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This direct-to-consumer stem cell marketplace has come under increasing scrutiny, but relatively little is known about the clinics that deliver these treatments or how the treatments they offer align with the expertise of the practitioners providing them. In a paper published August 1 in the journal Stem Cell Reports, investigators offer a detailed characterization of nearly 170 stem cell businesses across six southwestern states. The study focused on Arizona, California, Colorado, Nevada, New Mexico, and Utah, where the researchers estimate that about one-third of all stem cell clinics in the US are located.

“Previous studies have built up a broad picture of the direct-to-consumer stem cell industry,” says Emma Frow, an assistant professor in the School for the Future of Innovation in Society and the School of Biological and Health Systems Engineering at Arizona State University, co-first author on the paper along with David Brafman, also an assistant professor of bioengineering at Arizona State University.

“We took a deeper dive into a smaller number of clinics and found that there’s a lot of variation among the businesses offering these services,” she says. “About 25% focus exclusively on stem cells, but many others are facilities like orthopedic and sports medicine clinics that have added stem cells to their roster of services on offer. For these clinics, it’s very difficult to know how much of their business comes from stem cell treatments.”

The researchers conducted extensive online searches for stem cell clinics in the six states. “There’s no exhaustive list of all the clinics that exist,” Frow says. “This is a lively marketplace, with businesses opening and closing and changing their names.” For the 169 businesses they identified, they catalogued the treatments being offered, the medical conditions these clinics purported to treat, and the types of cells they claimed to use. For the 25% of clinics focused solely on stem cells, they also looked at the stated expertise of the care providers at these clinics in relation to the medical conditions they offer to treat with stem cells.

The researchers found that orthopedic, inflammatory, and pain conditions were the main types of medical conditions treated with stem cells at direct-to-consumer stem cell clinics in the Southwest. Frow notes that these types of conditions “tend to be chronic problems that often are not curable. The market has really capitalized on targeting conditions that are hard to manage with existing therapies.”

Earlier studies have shown a lower percentage of clinics treating inflammatory conditions. “This could mean that the number of clinics treating inflammatory conditions is on the rise or that, in the Southwest, there is more focus on treating inflammatory conditions than in other parts of the US,” Frow suggests.

The researchers also found differences in the degree to which the listed expertise of care providers at stem cell clinics matched the medical conditions they treat with stem cells. For example, they identified that specialists in orthopedics and sports medicine were more likely to restrict stem cell treatments to conditions related to their medical specialties, while care providers listing specialties in cosmetic or alternative medicine were more likely to treat a much wider range of conditions with stem cells.

Public discussions of direct-to-consumer stem cell treatments usually treat clinics as though their business models were all similar, but this study highlights some key differences across these clinics. “We think it makes a difference whether a business is focused solely on stem cells or offers it as one treatment among many,” Frow says. “And we think it’s important to pay attention to the medical qualifications and expertise of the care providers offering stem cell treatments. Just because someone is board certified doesn’t necessarily mean they are qualified to provide stem cell treatments. You really need to ask what they are board certified in and whether their medical expertise is well-matched to the condition you are seeking treatment for.”

Recent moves by the FDA to tighten up its guidelines and restrict the practices of these clinics have generated a lot of attention. The authors of this study see their work as contributing to these discussions. “We want to bring more transparency to discussions of the direct-to-consumer stem cell marketplace and to empower consumers to figure out what kinds of questions to ask when they’re considering treatment,” Frow says. “We also want to help the scientific community get a better understanding of the situation and to help the FDA and state medical boards think through their priorities with regards to regulating the market.”

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This research was funded by the Lincoln Center for Applied Ethics and the Institute for Social Science Research at Arizona State University.

Stem Cell Reports, Frow and Brafman et al.: “Characterizing direct-to-consumer stem cell businesses in the Southwest United States.” https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(19)30253-X

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Clinical trial shows alternate-day fasting a safe alternative to caloric restriction

Source: Cell Press
Date: 08/27/2019
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In recent years there has been a surge in studies looking at the biologic effects of different kinds of fasting diets in both animal models and humans. These diets include continuous calorie restriction, intermittent fasting, and alternate-day fasting (ADF). Now the largest study of its kind to look at the effects of strict ADF in healthy people has shown a number of health benefits. The participants alternated 36 hours of zero-calorie intake with 12 hours of unlimited eating. The findings are reported August 27 in the journal Cell Metabolism.

“Strict ADF is one of the most extreme diet interventions, and it has not been sufficiently investigated within randomized controlled trials,” says Frank Madeo, a professor of the Institute of Molecular Biosciences at Karl-Franzens University of Graz in Austria. “In this study, we aimed to explore a broad range of parameters, from physiological to molecular measures. If ADF and other dietary interventions differ in their physiological and molecular effects, complex studies are needed in humans that compare different diets.”

In this randomized controlled trial, 60 participants were enrolled for four weeks and randomized to either an ADF or an ad libitum control group, the latter of which could eat as much as they wanted. Participants in both groups were all of normal weight and were healthy. To ensure that the people in the ADF group did not take in any calories during fast days, they underwent continuous glucose monitoring. They were also asked to fill in diaries documenting their fasting days. Periodically, the participants had to go to a research facility, where they were instructed on whether to follow ADF or their usual diet, but other than that they lived their normal, everyday lives.

Additionally, the researchers studied a group of 30 people who had already practiced more than six months of strict ADF previous to the study enrollment. They compared them to normal, healthy controls who had no fasting experience. For this ADF cohort, the main focus was to examine the long-term safety of the intervention.

“We found that on average, during the 12 hours when they could eat normally, the participants in the ADF group compensated for some of the calories lost from the fasting, but not all,” says Harald Sourij, a professor at the Medical University of Graz. “Overall, they reached a mean calorie restriction of about 35% and lost an average of 3.5 kg [7.7 lb] during four weeks of ADF.”

The investigators found several biological effects in the ADF group:

* The participants had fluctuating downregulation of amino acids, in particular the amino acid methionine. Amino acid restriction has been shown to cause lifespan extension in rodents.

  • They had continuous upregulation of ketone bodies, even on nonfasting days. This has been shown to promote health in various contexts.
  • They had reduced levels of sICAM-1, a marker linked to age-associated disease and inflammation.
  • They had lowered levels of triiodothyronine without impaired thyroid gland function. Previously, lowered levels of this hormone have been linked to longevity in humans.
  • They had lowered levels of cholesterol.
  • They had a reduction of lipotoxic android trunk fat mass–commonly known as belly fat.

“Why exactly calorie restriction and fasting induce so many beneficial effects is not fully clear yet,” says Thomas Pieber, head of endocrinology at the Medical University of Graz. “The elegant thing about strict ADF is that it doesn’t require participants to count their meals and calories: they just don’t eat anything for one day.”

The investigators point to other benefits that ADF may have, compared with continuous calorie restriction. Previous studies have suggested calorie-restrictive diets can result in malnutrition and a decrease in immune function. In contrast, even after six months of ADF, the immune function in the participants appeared to be stable.

“The reason might be due to evolutionary biology,” Madeo explains. “Our physiology is familiar with periods of starvation followed by food excesses. It might also be that continuous low-calorie intake hinders the induction of the age-protective autophagy program, which is switched on during fasting breaks.”

Despite the benefits, the researchers say they do not recommend ADF as a general nutrition scheme for everybody. “We feel that it is a good regime for some months for obese people to cut weight, or it might even be a useful clinical intervention in diseases driven by inflammation,” Madeo says. “However, further research is needed before it can be applied in daily practice. Additionally, we advise people not to fast if they have a viral infection, because the immune system probably requires immediate energy to fight viruses. Hence, it is important to consult a doctor before any harsh dietary regime is undertaken.”

In the future, the researchers plan to study the effects of strict ADF in different groups of people including people with obesity and diabetes. They also plan to compare ADF to other dietary interventions and to further explore the molecular mechanisms in animal models.

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The research was primarily funded by the Austrian Science Fund; the Austrian Federal Ministry of Education, Science and Research; the University of Graz, and the field of excellence program BioHealth. Additional funding and declarations of interests can be found in the study.

Cell Metabolism, Stekovic, Hofer, and Tripolt et al.: “Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans.” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30429-2

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Researchers identify a gene linked to needing less sleep

Source: Cell Press
Date: 08/28/2019
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The genetics of circadian rhythms have been well studied in recent years, but much less is known about other types of genes that play a role in sleep, specifically those that regulate how much sleep our bodies require. Now, by studying a family with several members who require significantly less sleep than average, a team of researchers has identified a new gene that they believe has a direct impact on how much someone sleeps. They report their findings on August 28 in the journal Neuron.

“It’s remarkable that we know so little about sleep, given that the average person spends a third of their lives doing it,” says Louis Ptáček, a neurologist at the University of California, San Francisco (UCSF), and one of the paper’s two senior authors. “This research is an exciting new frontier that allows us to dissect the complexity of circuits in the brain and the different types of neurons that contribute to sleep and wakefulness.”

The family whose DNA led to the identification of this gene is one of several that Ptáček and UCSF geneticist Ying-Hui Fu, the paper’s other senior author, are studying and includes several members who function normally on only six hours of sleep. The gene, ADRB1, was identified using genetic linkage studies and whole-exome sequencing, which revealed a novel and very rare variant.

The first step in deciphering the role of the gene variant involved studying its protein in the test tube. “We wanted to determine if these mutations caused any functional alterations compared with the wild type,” Fu says. “We found that this gene codes for ß1-adrenergic receptor, and that the mutant version of the protein is much less stable, altering the receptor’s function. This suggested it was likely to have functional consequences in the brain.”

The researchers then conducted a number of experiments in mice carrying a mutated version of the gene. They found that these mice slept on average 55 minutes less than regular mice. (Humans with the gene sleep two hours less than average.) Further analysis showed that the gene was expressed at high levels in the dorsal pons, a part of the brain stem involved in subconscious activities such as respiration and eye movement as well as sleep.

Additionally, they discovered that normal ADRB1 neurons in this region were more active not only during wakefulness, but also during REM (rapid eye movement) sleep. However, they were quiet during non-REM sleep. Furthermore, they found that the mutant neurons were more active than normal neurons, likely contributing to the short sleep behavior.

“Another way we confirmed the role of the protein was using optogenetics,” Fu explains. “When we used light to activate the ADRB1 neurons, the mice immediately woke up from sleep.”

Ptáček acknowledges some limitations of using mice to study sleep. One of these is that mice exhibit different sleep patterns than humans, including, for example, sleeping in a fragmented pattern, rather than in a single continuous period. “But it’s challenging to study sleep in humans, too, because sleep is a behavior as well as a function of biology,” he says. “We drink coffee and stay up late and do other things that go against our natural biological tendencies.”

The investigators plan to study the function of the ADRB1 protein in other parts of the brain. They also are looking at other families for additional genes that are likely to be important. “Sleep is complicated,” Ptáček notes. “We don’t think there’s one gene or one region of the brain that’s telling our bodies to sleep or wake. This is only one of many parts.”

Fu adds that the work may eventually have applications for developing new types of drugs to control sleep and wakefulness. “Sleep is one of the most important things we do,” she says. “Not getting enough sleep is linked to an increase in the incidence of many conditions, including cancer, autoimmune disorders, cardiovascular disease, and Alzheimer’s.”

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This work was funded by the National Institute of Neurological Disorders and Stroke Informatics Center for Neurogenetics and Neurogenomics, the National Institutes of Health (NIH), and the William Bowes Neurogenetics Fund.

Neuron, Shi et al. “A rare mutation of β1-adrenergic receptor affects sleep/wake behaviors.” https://www.cell.com/neuron/fulltext/S0896-6273(19)30652-X

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Report cards on women in STEM fields finds much room for improvement

Source: Cell Press
Date: 09/05/2019
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Although women have made important contributions to science throughout history, they have consistently been underrepresented at all levels. Now, data from a four-year study of institutional “report cards” undertaken as part of the New York Stem Cell Foundation’s (NYSCF) Initiative on Women in Science and Engineering (IWISE) suggest that although a growing number of women are training in the sciences, efforts to promote and maintain women in more senior scientific roles are still largely inadequate. Additionally, the researchers report that not enough policies have been put in place to support women in science throughout their careers. The study is being reported September 5 in the journal Cell Stem Cell.

“The data suggest that we are making headway,” says Reshma Jagsi (@reshmajagsi), a radiation oncologist and director of the Center for Bioethics and Social Sciences in Medicine at the University of Michigan and one of the corresponding authors. “That said, there are still many institutions that have few women in senior-most faculty positions. There also remains quite a bit of room for improvement in certain areas, including the representation of women in certain roles, such as speaking at scientific meetings.”

The researchers obtained their data through the use of institutional report cards that were collected when individual researchers applied for grants from NYSCF. The report cards were part of a 2014 NYSCF project that put forward a number of strategies aimed at helping to achieve gender parity in science, technology, engineering, and math (STEM). Of the 1,287 report cards that were submitted, 741 provided complete information for a given year, and some included multiple years. Overall, the data in the paper represent 541 institutions in 38 countries in North America (72%) and Europe (18%).

The investigators found that although women made up more than half of the population among undergraduate, graduate, and post-graduate students, the picture became different as seniority increased. Women made up 42% of assistant professors, 34% of associate professors, and 23% of full professors. These rates varied greatly by institution: At about one-third of the institutions surveyed, women made up less than 10% of tenured faculty recruits.

“We expected to find that women would be better represented at more junior ranks compared with senior ranks,” Jagsi says. “But I found it noteworthy that there were regional differences. For example, institutions in Europe come closer to achieving gender parity.”

The researchers say their findings suggest that the primary issue is not recruiting women into STEM roles but retaining them and promoting them into more influential positions.

They also point out the important part that funding organizations can play. “Funding organizations are in a unique position to require institutional leaders to pay attention to equity, diversity, and inclusion within their organizations,” Jagsi says. “By requiring these report cards, they can promote actions that help all scientists thrive. We hope that other funding bodies, like the NIH, will adopt a similar report card.”

The next phase of IWISE will focus on highlighting best practices undertaken by institutions. This will provide comparative data and allow the researchers to monitor progress over time. The researchers will also look at other factors that may influence the recruitment and retention of women scientists, such as the presence of women in top leadership roles, the rates at which tenured women stay in their positions, and equity in salaries across gender, race, and ethnicity.

“For my own work, I plan to begin to focus more on issues of intersectionality,” Jagsi concludes. “A particularly understudied area involves the career experiences in women with other minority identities, such as race. Further research is needed to understand the challenges these women face.”

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This study was supported by the Doris Duke Charitable Foundation and the New York Stem Cell Foundation Research Institute.

Cell Stem Cell, Beeler et al. “Institutional Report Cards for Gender Equality Results of a 4-Year Pilot to Encourage Benchmarking for Women in STEM.” https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30345-5

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Researchers alter mouse gut microbiomes by feeding good bacteria their preferred fibers

Source: Cell Press
Date: 09/19/2019
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Humans choose food based on the way it looks, smells, and tastes. But the microbes in our guts use a different classification system–one that is based on the molecular components that make up different fibers. In a study published September 19 in the journal Cell, investigators found particular components of dietary fiber that encourage growth and metabolic action of beneficial microbes in the mouse gut.

The research aims to develop ways to identify compounds that can enhance the representation of health-promoting members of the gut microbial community. The goal is to identify sustainable, affordable dietary fiber sources for incorporation into next-generation, more nutritious food products.

“Fiber is understood to be beneficial. But fiber is actually a very complicated mixture of many different components,” says senior author Jeffrey Gordon, a microbiologist at the Washington University School of Medicine in St. Louis. “Moreover, fibers from different plant sources that are processed in different ways during food manufacturing have different constituents. Unfortunately, we lack detailed knowledge of these differences and their biological significance. We do know that modern Western diets have low levels of fiber; this lack of fiber has been linked to loss of important members of the gut community and deleterious health effects.”

The researchers started by testing 34 food-grade fiber preparations, many purified from byproducts of food manufacturing such as peels from fruits and vegetables that are thrown out during production of processed foods and drinks. They used mice initially raised under sterile conditions and then colonized with human gut microbes. The animals were fed a high-fat, low-fiber diet representative of diets typically consumed in the United States, with or without different types of supplemental fibers. The goal was to identify those fibers that were best at boosting the levels of key fiber-degrading bacterial species and promoting the expression of beneficial metabolic enzymes in the microbiome.

Since the mice had been colonized with a defined collection of human gut bacteria with sequenced genomes, the researchers knew all the genes that were present in their model human gut microbial community. This allowed them to perform a comprehensive, high-resolution proteomics study of all bacterial proteins whose expression changed in response to the different fiber types they tested. Combining these results with genetic screens, they were able to identify particular fiber sources, their bioactive molecular components, and the bacterial genes that increased for different Bacteroides species when they encountered different fibers. They focused on Bacteroides because members of this group of bacterial species contain genes responsible for metabolizing dietary fiber that are not present in the human genome.

For the second phase of the study, the investigators wanted to determine how different members of the microbial community interact with each other as they dine on dietary fiber. First author Michael Patnode, a postdoctoral fellow in Gordon’s lab, developed fluorescently labeled artificial food particles with different types of bound carbohydrates from different fibers. Collections of these nutrient-containing particles were fed to mice colonized with defined microbial communities containing different combinations of Bacteroides species.

“We were excited to see how these ‘biosensors’ could be used to assess the processing of particular fiber components by particular bacterial species,” Patnode says. By feeding these particles to mice that either carried or did not carry a dominant fiber-consuming species, the authors found that subordinate species were waiting in line to step up and consume the fiber.

“We had suspected there might be competition going on among the different strains and that some would be stronger competitors than others,” Patnode says. Proteomics analyses and genetic screens confirmed that there was a hierarchy of fiber consumption among the species present in this model bacterial community.

Gordon explains that “it’s important to understand how the presence of a particular organism affects the dining behavior of other organisms–in this case, with regard to different fibers. If we are going to develop microbiota-directed foods aimed at providing benefits to human health, it’s important to find ways to determine which food staples will be the best source of nutrients and how the microbiota will respond.”

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This work was supported by the National Institutes of Health, Mondelez International, and the U.S. Department of Energy. Gordon is a co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. Elements of this report are the subject of patent applications that are currently being submitted.

Cell, Patnode et al.: “Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans” https://www.cell.com/cell/fulltext/S0092-8674(19)30899-2

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Important gene variants found in certain African populations

Source: Cell Press
Date: 10/31/2019
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In the nearly 20 years since the Human Genome Project was completed, experts in genetic variants increasingly have raised concerns about the overemphasis on studying people of European descent when performing large population studies. A study appearing October 31 in the journal Cell aims to address some of this disparity by focusing on populations living in rural Uganda, thus revealing several new genetic variants related to human health.

“This study highlights the high level of diversity in African populations that remains undiscovered despite large numbers of gene sequences that have been generated from Europeans,” says co-senior author Manjinder Sandhu, who studies genomic diversity at the University of Cambridge in the UK. “We found that more than a quarter of the genetic variation we observed in the Ugandan population had not been discovered.”

The participants in the study came from 25 villages in a rural part of southwestern Uganda. Using blood samples, the investigators generated genotypes from about 5,000 individuals and conducted whole-genome sequencing on about 2,000 individuals. The researchers collected information through electronic questionnaires; carried out physical measurements such as blood pressure, height, and weight; and tested the blood samples for medically important markers such as cholesterol and glucose.

The investigators made several findings related to genetic variants and health. “We found many new associations with blood traits, liver function tests, and glucose-related traits,” Sandhu says. “Most of these relate to genetic variants that are either unique to Africans or rare in non-Africans. They may not have been readily discovered even in very large studies of non-African populations.”

Specifically, they found that height is less genetically determined among rural Ugandans relative to what’s been seen in European studies. In contrast, LDL cholesterol levels appear to be more genetically determined relative to Europeans.

“We think this might relate to differences in the impact of diet and nutrition relative to genetic influences between African and European populations,” says co-first author Deepti Gurdasani, a career development fellow at Queen Mary’s University of London. “For example, the genetic influences on height might be more limited by malnutrition in early childhood in these populations. On the other hand, so-called Western dietary patterns possibly have a lower influence on cholesterol levels, making these more genetically determined.”

The researchers also found an association between a genetic variant that causes alpha-thalassemia among Africans and levels of glycated hemoglobin. This genetic variant, found in 22% of Africans, protects against severe malaria. It is rare in populations where malaria isn’t endemic. “Because glycated hemoglobin is commonly used to diagnose diabetes, this finding suggests that it needs careful evaluation as a test for diabetes in relevant populations,” says co-senior author Ayesha Motala, of KwaZulu Natal University in South Africa.

The study also revealed important findings about human history and migration. “Uganda is a melting pot of different cultures and languages, and we wanted to understand the genetic structure and history of populations within the country,” says Pontiano Kaleebu, the Director of Uganda Virus Research Institute and Director of the MRC/UVRI & London School of Hygiene and Tropical Medicine Uganda Research Unit, who co-led the project. “These studies highlight the extensive movement and population expansions that have occurred within and into Africa over the past few thousand years.”

Analysis revealed that the genomes of Ugandans are a mosaic of many ancestries, likely reflecting the extensive migration from surrounding regions spanning hundreds to thousands of years. It also showed that significant Eurasian ancestry has entered the region at multiple time points, ranging from a few hundred years ago to about 4,000 years ago.

Although the researchers identified new genetic variants associated with disease, they say much more research is needed to understand how these genetic variants affect disease traits. This will require not just looking at genomes but also at functional effects of genomes on gene expression and protein levels.

In the future, they also plan to look at individuals from other parts of Africa, especially indigenous hunter-gatherer populations such as the Khoe-San populations in Namibia and South Africa and the rainforest hunter-gatherer populations in central Africa.

“This study confirms that genetic causes of disease may be different in Africans and provides opportunities to identify new genes associated with disease that would not be identified in European studies,” Gurdasani concludes. “This kind of research will allow us to identify new targets for therapies that could potentially be useful for all populations.”

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This work was funded by the Wellcome Trust, the Wellcome Sanger Institute, the UK Medical Research Council, and the Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine Uganda Research Unit core funding. This work was funded in part by IAVI with the generous support of the United States Agency for International Development and other donors.

Cell, Gurdasani et al. “Uganda Genome Resource enables insights into population history and genomic discovery in Africa” https://www.cell.com/cell/fulltext/S0092-8674(19)31120-1

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Two ocean studies look at microscopic diversity and activity across entire planet

Source: Cell Press
Date: 11/14/2019
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  • Two papers publishing in the journal Cell use samples and data collected during the Tara Oceans Expedition to analyze current ocean diversity across the planet, providing a baseline to better understand the future impacts of climate change on the oceans.
  • Ibarbalz et al. report that most planktonic groups follow a gradient of diversity along latitudes, with the lowest level of diversity closest to the poles.
  • Salazar et al. find that microbial diversity and microbial gene expression play different roles in how ocean microbial communities respond to environmental change in different geographies.
  • In a Perspective publishing in the journal One Earth, Claudet et al. examine the barriers that have prevented ocean sustainability policy changes so far and suggest strategies for leveraging the UN Decade of Ocean Science for Sustainable Development to overcome these challenges.

In an effort to reverse the decline in the health of the world’s oceans, the United Nations (UN) has declared 2021 to 2030 to be the Decade of Ocean Science for Sustainable Development. One key requirement for the scientific initiative is data on existing global ocean conditions. An important trove of data is already available thanks to the Tara Oceans expedition, an international, interdisciplinary enterprise that collected 35,000 samples from all the world’s oceans between 2009 and 2013. The samples were collected by researchers aboard one schooner, the Tara, at depths ranging from the surface to 1,000 meters deep.

Two papers being published November 14 in the journal Cell are the latest to use samples and data collected during the Tara Oceans expedition to analyze diversity across the entire planet of plankton, microscopic organisms that drift on oceanic currents that are key for the well-being of our oceans. One study focused on the diversity of plankton across Earth’s oceans, whereas the other study assessed gene expression among microbial communities as a way to predict how these communities might adapt to changing environmental conditions.

Plankton Diversity across Different Latitudes

“Everything in the ocean is connected, which means it has the potential to move around,” says Chris Bowler, a National Center for Scientific Research (CNRS) scientist at the Institut de Biologie de l’Ecole Normale Superieure (IBENS) in Paris and a co-senior author of the plankton study. “This makes it important to assemble everything on a global scale. Doing deep analysis also allows us to catch the rare organisms in the biosphere in addition to those that are more abundant.”

“Our study focused on plankton because it’s a major contributor to marine ecosystems in terms of biomass, abundance, and diversity,” says co-senior author Lucie Zinger of IBENS. “All types of life have representatives in the plankton–bacteria, archaea, protists, animals and plants, as well as viruses. But the large majority of this diversity is invisible to the naked eye.”

The paper reports that the large majority of planktonic groups, from giant viruses to small animals, follow a gradient of diversity along latitudes, with the lowest level of diversity closest to the poles. “Ocean temperature is mainly responsible for this pattern,” Zinger notes. “Ocean warming due to climate change is likely to lead to a ‘tropicalization,’ or increase, of plankton diversity in temperate and polar waters. The consequences of this are still unclear, but we know these geographic areas are currently very important for different ecosystem services, including fisheries and carbon sequestration.”

One innovative aspect of this study was that it combined both imaging and DNA-based techniques to assess plankton diversity. “We know a lot about how to process information from DNA sequences,” Bowler says. “But images are much more complicated. We observed many different morphologies and different behaviors of these organisms. There are many new organisms and new kinds of interactions between them still to be discovered.”

Understanding the Activity of Microbial Life at Different Ocean Depths and Geographies

The transcriptome study combined metagenomic and metatranscriptomic data, allowing the team to analyze the analyze which genes were present, as well as which genes were turned on, in ocean microbial communities across gradients of both depth and latitude. Previous studies on the diversity of marine microbial life have focused primarily on genomes. This was the first to look at transcriptomes on a global scale.

“Looking at transcriptomes is important for determining not just which microbes are present, but what those microbes are actually doing with regard to activities like photosynthesis and nutrient uptake,” says senior author Shinichi Sunagawa of the Institute of Microbiology and Swiss Institute of Bioinformatics at ETH Zurich. “One of our goals was to learn whether microbial communities adjust to environmental and temperature variations with changes in their composition relative to each other or with changes in the gene expression patterns within these communities.”

The investigators found that in terms of taxonomic, genomic, and transcriptomic composition, there are distinct ecological boundaries separating both surface water from deep water and polar from nonpolar regions. They expected to see some of these changes–such as differences in the levels of photosynthetic organisms relative to water depth. But some other observations were rather unexpected.

“We did not expect to find biogeographic patterns for the underlying mechanisms of metatranscriptomic composition variation. Specifically, we found differences in polar communities to be dominated by changes in organismal composition, while in nonpolar waters, the differences were dominated by changes in the expression of genes,” Sunagawa says. He adds that his team was also surprised to find genomic and transcriptomic evidence for a nitrogen-fixing bacterium in deep Arctic waters.

“Every drop of marine water is full of microbes, which play a central role in many processes relevant to life on Earth,” he notes. “Understanding the ecological factors that determine the diversity, composition, and activity of these organisms is essential to better model and predict future deviations, especially in light of climate change.”

One limitation of the data to come from the Tara Oceans expedition is that the samples were collected over a relatively short period of time, less than four years. This makes it difficult to observe any measurable trends in today’s oceans related to climate change. The researchers say that longer-term studies are needed to account for changes in factors like acidification, deoxygenation, and pollution.

A Call for Ocean Science in the Face of Climate Change

Researchers examine the barriers that have prevented ocean sustainability policy changes so far and suggest strategies for overcoming these challenges in a Perspective publishing November 14 in the new Cell Press journal One Earth.

“As revealed by the releases of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services global assessment and of the Special Report on the Ocean and Cryosphere of the IPCC, both in 2019, there is now an urgency to engage into sustainable pathways,” says corresponding author Joachim Claudet of the CNRS. He adds that the main threats on the ocean’s sustainability are overexploitation of fish, shellfish, and other organisms; land- and sea-based pollution; and land/sea-use change, including coastal development for infrastructure and aquaculture; and climate change.

“We need science to develop evidence that can better inform policies to implement viable solutions, as well as operational and transformative actions that can better impact societies, from local to global scales,” he says. “The Tara expeditions have multiple values. They allow us to collect local natural, chemical, and physical in situ data at the ocean scale. These data can feed into both basic and applied research. Tara’s outreach programs can also be a driver of the most needed change in perception that the ocean is both highly valuable and vulnerable.”

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This work was primarily funded by the Tara Ocean Foundation and 23 supporting institutes (https://oceans.taraexpeditions.org/). For additional funding information, please see individual papers.

Cell, Ibarbalz et al.: “Global Trends in Marine Plankton Diversity across Kingdoms of Life” https://www.cell.com/cell/fulltext/S0092-8674(19)31124-9 DOI: 10.1016/j.cell.2019.10.008

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Simulations suggest embryo selection based on traits like height or IQ is still far off

Source: Cell Press
Date: 11/21/2019
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There have been concerns about the idea of “designer babies” for almost as long as in vitro fertilization and technology to screen embryos for inherited disorders have existed. While the recent live births resulting from human embryonic CRISPR editing have heightened global attention to these issues, currently, the most practical approach to genetic “enhancement” of embryos is preimplantation genetic screening of IVF embryos. But according to a study publishing November 21 in the journal Cell, the ability to select for traits that are brought about by multiple genes–rather than genetic diseases caused by a single mutation–is more far off and complicated than most people probably realize.

“The ability to do genomic sequencing of embryos is much easier than it was even five years ago, and we know many more gene variants linked to certain traits,” says co-corresponding author Shai Carmi, of the Hebrew University of Jerusalem. “But selecting embryos for particular traits is very controversial except when it relates to a serious disease like cystic fibrosis. It raises many issues related to eugenics and unequal opportunities.”

Carmi’s team looked at the feasibility of selecting embryos based on each of two traits caused by multiple genes–IQ and height–as a kind of thought experiment. While there are many traits determined by multiple genes that the researchers could have investigated, they chose to focus on IQ because it is frequently brought up in concerns regarding eugenics and on height because it is objectively measurable and a lot is known about the complex genetics influencing height. Their findings suggest that our current knowledge of the genetics of these types of traits may not be enough to generate a substantial increase in the desired traits in an IVF embryo selection scenario.

In the study, the researchers ran computer simulations using genomic sequences from real people to model genomic profiles of hypothetical embryos that would result from pairs of those people–some actual couples and some artificially paired. In the simulations, they assumed that each couple would have ten embryos to choose from. They then predicted the IQ or adult height for each of the offspring based on the gene variants present in the genomes of the simulated embryos. Their experiments were based on the assumption that the embryo with the top score could then be selected for implantation.

They found that expected advantages to these theoretical offspring would be relatively small. For IQ, the most it increased above the average of the embryos was three points. For height, the most it increased above the average was three centimeters.

And even if some people might believe that those increases were great enough to warrant using the technology, they are not guaranteed.

“There is much about these traits that is unpredictable,” Carmi says. “If someone selected an embryo that was predicted to have an IQ that was two points higher than the average, this is no guarantee it would actually result in that increase. There is a lot of variability that is not accounted for in the known gene variants.”

There are several other limitations, Carmi notes, that would make it challenging to accurately select embryos for desired traits.

For one, the researchers conducted their simulations using ten embryos from each couple, but in reality, many couples get far fewer viable embryos when they do in vitro fertilization. For example, with five embryos, the gain would be reduced to 2.5 IQ points or 2.5 cm. When they based the simulation on 50 or 100 embryos, they found that the benefit per embryo decreased as the number of embryos increased, indicating diminishing returns even with large numbers of hypothetical embryos to choose from.

In addition, what is known about the gene variants linked to traits like height and IQ–as well as other health-related traits like blood pressure and cholesterol–applies mainly to people of European descent. They would be much less applicable for people from other parts of the world. Finally, attempting to maximize more than one trait, a potential future scenario, would make embryo selection far more complicated: an embryo that ranked highest for IQ may rank lowest for height, for example.

Furthermore, the researchers used real-world data to confirm that predictions about traits made using what’s currently known about gene variants are not always accurate. They reported on an analysis of 28 families with up to 20 children who have grown to adulthood–and found that the offspring they would have selected for having the greatest height based on gene variants was not always the tallest one in adulthood.

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This research was supported by the Abisch-Frenkel Foundation, the National Institutes of Health, and the James S. McDonnell Centennial Fellowship in Human Genetics.

Cell, Karavani et al.: “Screening human embryos for polygenic traits has limited utility” https://www.cell.com/cell/fulltext/S0092-8674(19)31210-3

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Pilot study finds time-restricted eating has benefits for people at risk for diabetes

Source: Cell Press
Date: 12/05/2019
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Previous studies have looked at employing time-restricted eating (TRE), a form of intermittent fasting, as a way to lose weight and improve health measures such as blood sugar and blood pressure in mice and healthy people. But in a study publishing December 5 in the journal Cell Metabolism, researchers for the first time looked at the effects of TRE in people who had been diagnosed with metabolic syndrome and therefore were at a higher risk of diabetes, heart disease, and stroke. The investigators found that when participants restricted their eating to 10 hours or less over a period of 12 weeks, they lost weight and some symptoms of metabolic syndrome improved.

“There has been a lot of discussion about intermittent fasting and what time window people should eat within to get the benefits of this kind of diet,” says co-corresponding author Satchidananda Panda, a Professor at the Salk Institute. “Based on what we’ve observed in mice, a 10-hour time window seems to convey these benefits. At the same time, it’s not so restrictive that people can’t follow it long-term.”

Metabolic syndrome is characterized by having three or more of five specific risk factors: high fasting blood sugar, high blood pressure, high triglyceride levels, low HDL (“good”) cholesterol, and abdominal obesity. People with metabolic syndrome are at greatly increased risk of developing more severe health problems, including diabetes, heart disease, and stroke.

“As a preventive cardiologist, I try to work with my patients and encourage them to make lifestyle changes, but it is very hard to get them to make lasting and meaningful changes,” says co-corresponding author Pam Taub, a cardiologist and Associate Professor of Medicine at the University of California San Diego School of Medicine. “When someone has been diagnosed with metabolic syndrome, this is a critical window for intervention. Once people become diabetic or are on multiple medications such as insulin, it’s very hard to reverse the disease process.”

In the study, 19 individuals with metabolic syndrome were recruited to participate in a program of TRE for three months. They were told they could decide what time to eat and how much to eat as long as all food consumption occurred within a 10-hour window. Most of the people in the study were obese and 84% were taking at least one medication, like a statin or antihypertensive.

At the end of the 12 weeks, the participants had an average of a 3% reduction in their weight and body mass index (BMI) and a 3% reduction in abdominal/visceral fat. Many also had reductions in cholesterol and blood pressure and improvements in fasting glucose.

Participants in the study used an app created by Panda called myCircadianClock (mCC) to log the times they ate and also to track their sleep. They also wore activity monitors that measured their sleeping and waking patterns and a glucose monitor that continuously tracked their glucose levels.

“We told people that they could choose when they ate their meals, as long as they remained within the 10-hour window,” Panda says. “We found that universally, they chose to eat breakfast later, about two hours after waking, and to eat dinner earlier, about three hours before going to bed.” He notes that in addition to the improvements seen in body weight and measures of metabolic syndrome, 70% of the participants also reported an increase in sleep satisfaction or in the amount they slept.

Taub says that the participants, about half of whom were already her patients, also reported generally having more energy, and some were able to have their medications lowered or stopped after completing the study. Overall, they told her that the plan was easier to follow than counting calories or embarking on an exercise program. More than two-thirds of participants continued with TRE for up to a year after the study was over, at least part of the time, she says.

Based on this pilot study, Taub and Panda have already begun a randomized, controlled clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to confirm the benefits of TRE in people with metabolic syndrome. They plan to recruit more than 100 participants–half for each arm. They also intend to conduct additional research to look at other physiological responses to TRE, including effects on the mitochondria in skeletal muscle and changes in liver function.

For anyone considering trying TRE, Taub recommends they first consult with a physician. This is especially important for anyone with metabolic syndrome who is already taking medication, she notes. “Any time someone is losing weight, they need to check with their doctor about whether their medications need to be adjusted,” she says. “For instance, if a patient is on blood pressure medications and they lose a significant amount of weight their blood pressure medication needs to be lowered.”

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This study was funded by a University of California San Diego Public Health Pilot Grant, an American College of Cardiology (ACC)/Merck Research Fellowship Award, a Larry L. Hillblom Foundation Postdoctoral Fellowship, a Salk Women in Science Fellowship, the Department of Homeland Security, the Department of Defense, the Leona M. and Harry B. Helmsley Charitable Trust, the Robert Wood Johnson Foundation, and the National Institutes of Health.

Cell Metabolism, Wilkinson et al.: “Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30611-4