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Researchers propose widespread banking of stool samples for fecal transplants later in life

Source: Cell Press
Date: 6/30/2022
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Changes in the way that humans live and eat have resulted in tremendous alterations in the gut microbiome, especially over the past few decades. These changes have been linked to increased rates of asthma, allergies, diseases of the digestive system, type 2 diabetes, and other conditions. In an opinion article published June 30 in the journal Trends in Molecular Medicine, a team from Harvard Medical School and Brigham and Women’s Hospital (BWH) proposes that we can combat these trends by having individuals bank samples of their own gut microbiota when they are young and healthy for potential use later in life in an autologous fecal microbiota transplant (FMT).

“The idea of ‘rewilding’ the human microbiome has taken off in recent years and has been hotly debated from medical, ethical, and evolutionary perspectives,” says corresponding author Yang-Yu Liu, an Associate Professor of Medicine at Harvard and an Associate Scientist in the Channing Division of Network Medicine at BWH. “It is still unknown if people in industrialized societies can gain some health benefit by restoring their microbiome to an ancestral state. In this paper, we proposed a way to rejuvenate the human gut microbiome.”

FMTs using donor stool have shown benefit for treating some conditions, primarily infections with Clostridioides difficile (C. diff), which affect about half a million people and kill about 29,000 in the United States every year. However, one limitation of using donor stool is variability in the host’s response, likely due to genetic and environmental differences between the donor and host.

Efforts in Yang’s lab focus on understanding the ecological dynamics and organizational principles of the human microbiome to inform the design of microbiome-based therapeutics. OpenBiome, a nonprofit stool bank based in Somerville, Massachusetts, is the first stool bank to offer an option for individuals to bank their own stool for future treatment of C. diff infection. Yang and his colleagues looked at whether this approach might be feasible on a large scale for many other diseases.

“Conceptually, the idea of stool banking for autologous FMT is similar to when parents bank their baby’s cord blood for possible future use,” says Yang. “However, there is greater potential for stool banking, and we anticipate that the chance of using stool samples is much higher than for cord blood.”

“But there are many practical issues to implementing this idea,” says Yang. The article takes a closer look at some of those issues, including optimal storage methods, how much stool should be banked, and what the costs might be.

“Autologous transplants would naturally avoid or at least mitigate donor-recipient compatibility issues, but a major disadvantage of autologous transplants is the need for long-term cryopreservation of stool samples, typically requiring liquid nitrogen storage,” says co-author Shanlin Ke, a postdoctoral research fellow in Yang’s lab. “The long-term safe storage and subsequent resuscitation and cultivation of stool samples is a fundamental research question by itself. To inform practical guidelines for stool banking, further research is needed to systematically test longer storage times and preservation, resuscitation, and cultivation procedures.”

Yang acknowledges that widespread banking could lead to a system in which those with more financial resources are more likely to have banked stool for future use. “We do not anticipate that all individuals in our society are willing or able to pay the cost associated with the service of ‘rejuvenating’ their gut microbiome, in the same way that not all parents pay the cost of cord blood banking for their newborns,” he says. “But as scientists our job is to provide a scientific solution that may eventually benefit human well-being. Developing a reasonable business model and pricing strategy so that the solution is affordable to everyone would require the joint force of entrepreneurs, scientists, and perhaps governments.”

“Autologous FMTs have the potential to treat autoimmune diseases like asthma, multiple sclerosis, inflammatory bowel disease, diabetes, obesity, and even heart disease and aging,” says co-author Scott T. Weiss, a Professor of Medicine at Harvard and Associate Director of the Channing Division of Network Medicine at BWH. “We hope this paper will prompt some long-term trials of autologous FMTs to prevent disease.”

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Cultural Barriers to Genetic Testing

Source: Cell Press
Date: 6/7/2022
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As prices for genetic testing go down and awareness of what these tests can do goes up, more and more people are choosing to have their DNA analyzed. The underrepresentation of non-European ancestry groups in genomic databases, however, complicates the interpretation of their genetic test results.

In a commentary published on June 2 in the American Journal of Human Genetics(link is external and opens in a new window), researchers examine how “variants of uncertain significance” (VUS)—a genetic change whose impact on the individual’s disease risk is not yet known—are more likely to be identified in populations underrepresented in genetic databases, as well as ways to reduce their incidence.  

“A great deal of effort goes into broad-based projects that aim to recruit diverse segments of the population,” says first author Paul Appelbaum, MD, director of the Center for Research on Ethical, Legal & Social Implications of Psychiatric, Neurologic & Behavioral Genetics at Columbia University. “What’s different about our contribution here is the recognition that broad-based recruitment will need to be complemented by more focused efforts that take group concerns into account.”

There are practical and ethical reasons that VUS are important to address. Tests that yield a VUS fail to generate information that is useful clinically. Additionally, although current guidelines discourage clinicians from making treatment decisions based on a VUS, many clinicians and patients may feel compelled to act on them anyway. Discovery of a VUS can lead to anxiety, distress—especially variants in genes known to increase the risk of diseases like cancer—and, in some cases. even drastic interventions like prophylactic surgery.

Cultural Concerns

In this paper, the investigators focused on cultural issues among two ancestry groups, as well as culturally informed ways to address and overcome those issues.

For the first group—the Sephardi Jewish community in New York—they focus on the Dor Yeshorim project, an effort created to reduce the incidence of genetic diseases in the Jewish community, with an initial focus on Tay Sachs. The second group was the Silent Genomes Project, an effort housed at the University of British Columbia that aims to reduce healthcare disparities and improve diagnostic success for children with genetic diseases from Indigenous populations in Canada.

The two communities have very different concerns about contributing to genomic research and datasets. Sephardi concerns focus on the possible negative effects of genetic findings on the marriage prospects of family members. Canadian Indigenous populations seek control over the research uses to which their genetic data would be put.

“Both groups have specific cultural reasons for being hesitant to provide genetic data,” says Dr. Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law at Columbia. “By working with them to find ways to address their concerns, we can overcome these hesitations.” 

Dr. Appelbaum acknowledges challenges in scaling up these kinds of efforts to reach other underrepresented populations and the lack of a one-size-fits-all approach. “For each of these groups, we need to recognize the reasons for their underrepresentation and work with them to find ways to address those concerns,” he says. He adds that it’s vital to obtain more funding for targeted recruitment efforts and to develop a governance structure that involves the relevant communities in an ongoing fashion.

“It’s crucial to know the frequency of variants in the population,” Dr. Appelbaum says. “And given differences in variant frequency across population groups and the prevalence of population-specific variants, comparisons with reference data from a specific ancestral group may be crucial. That’s true in both clinical settings and in research.”

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Climate change likely to reduce the amount of sleep that people get per year

Source: Cell Press
Date: 5/20/2022
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Most research looking at the impact of climate change on human life has focused on how extreme weather events affect economic and societal health outcomes on a broad scale. Yet climate change may also have a strong influence on fundamental daily human activities — including a host of behavioral, psychological, and physiological outcomes that are essential to wellbeing. In a study published May 20th in the journal One Earth, investigators report that increasing ambient temperatures negatively impact human sleep around the globe.

The team says their findings suggest that by the year 2099, suboptimal temperatures may erode 50 to 58 hours of sleep per person per year. In addition, they found that the temperature effect on sleep loss is substantially larger for residents from lower income countries as well as in older adults and females.

“Our results indicate that sleep — an essential restorative process integral for human health and productivity — may be degraded by warmer temperatures,” says first author Kelton Minor of the University of Copenhagen. “In order to make informed climate policy decisions moving forward, we need to better account for the full spectrum of plausible future climate impacts extending from today’s societal greenhouse gas emissions choices.”

It’s long been known that hot days increase deaths and hospitalizations and worsen human performance, yet the biological and behavioral mechanisms underlying these impacts have not been well understood. Recent self-reported data from the United States have suggested that subjective sleep quality decreases during periods of hot weather, but how temperature fluctuations may impact changes in objective sleep outcomes in people living across a variety of global climates has remained unclear.

“In this study, we provide the first planetary-scale evidence that warmer-than-average temperatures erode human sleep,” Minor says. “We show that this erosion occurs primarily by delaying when people fall asleep and by advancing when they wake up during hot weather.”

To conduct this research, the investigators used anonymized global sleep data collected from accelerometer-based sleep-tracking wristbands. The data included 7 million nightly sleep records from more than 47,000 adults across 68 countries spanning all continents except for Antarctica. Measures from the type of wristbands used in this study had previously been shown to align with independent measures of wakefulness and sleep.

The study suggested that on very warm nights (greater than 30 degrees Celsius, or 86 degrees Fahrenheit), sleep declines an average of just over 14 minutes. The likelihood of getting less than seven hours of sleep also increases as temperatures rise.

“Our bodies are highly adapted to maintain a stable core body temperature, something that our lives depend on,” Minor says. “Yet every night they do something remarkable without most of us consciously knowing — they shed heat from our core into the surrounding environment by dilating our blood vessels and increasing blood flow to our hands and feet.” He adds that in order for our bodies to transfer heat, the surrounding environment needs to be cooler than we are.

Early controlled studies in sleep labs found that both humans and animals sleep worse when the room temperature is too hot or too cold. But this research was limited by how people act in the real world: they modify the temperature of their sleeping environment to be more comfortable.

In the current research, the investigators found that under normal living routines, people appear far better at adapting to colder outside temperatures than hotter conditions. “Across seasons, demographics, and different climate contexts, warmer outside temperatures consistently erode sleep, with the amount of sleep loss progressively increasing as temperatures become hotter,” Minor says.

One important observation was that people in developing countries seem to be more affected by these changes. It’s possible that the greater prevalence of air conditioning in developed countries could play a role, but the researchers could not definitively identify the reason because they did not have data on air conditioning access among subjects. The researchers also note that because they uncovered compelling evidence that the impact of warming temperatures on sleep loss is unequal globally, new research should especially consider more vulnerable populations, particularly those residing in the world’s hottest — and historically poorest — regions.

In future work, the team would like to collaborate with global climate scientists, sleep researchers, and technology providers to extend the scope of global sleep and behavioral analyses to other populations and contexts. Additionally, they are interested in studying the impact of rising outdoor temperatures on the sleep outcomes of incarcerated populations situated in hot climates, who may have particularly limited access to air conditioning.

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Distinct biological ages across individuals’ various organs and systems

Source: Cell Press
Date: 3/8/2022
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It’s common to say that someone looks either younger or older than their chronological age, but aging is more than skin deep. Our various organs and systems may have different ages, at least from a biological perspective. In a study published March 8 in the journal Cell Reports, an international team of investigators used biomarkers, statistical modeling, and other techniques to develop tools for measuring the biological ages of various organ systems. Based on their findings, the researchers report that there are multiple “clocks” within the body that vary widely based on factors including genetics and lifestyle in each individual.

“Our study used approaches that can help improve our understanding of aging and — more importantly — could be used some day in real healthcare practice,” says co-corresponding author Xun Xu of the Beijing Genomics Institute (BGI) and China National GeneBank (CNGB) in Shenzhen, China. “We used biomarkers that could be identified from blood and stool samples plus some measurements from a routine body checkup.”

The concept of evaluating people’s biological aging rates has been around since the 1970s, but earlier studies were focused either on developing methods for estimating one centralized aging index or studying the molecular aging biomarkers using tissues and cell cultures outside the body.

“There has been a lack of practical applications in a population-based sample for precisely estimating the aging rates of live people’s organs and systems,” says co-corresponding author Xiuqing Zhang, also of BGI and CNGB. “So we decided to design one.”

To do this research, the investigators recruited 4,066 volunteers living in the Shenzhen area to supply blood and stool samples and facial skin images and to undergo physical fitness examinations. The volunteers were between the ages of 20 and 45 years; 52% were female and 48% were male. “Most human aging studies have been conducted on older populations and in cohorts with a high incidence of chronic diseases,” says co-corresponding author Brian Kennedy of the National University of Singapore. “Because the aging process in young healthy adults is largely unknown and some studies have suggested that age-related changes could be detected in people as young as their 20s, we decided to focus on this age range.”

In total, 403 features were measured, including 74 metabolomic features, 34 clinical biochemistry features, 36 immune repertoire features, 15 body composition features, 8 physical fitness features, 10 electroencephalography features, 16 facial skin features, and 210 gut microbiome features. These features were then classified into nine categories, including cardiovascular-related, renal-related, liver-related, sex hormone, facial skin, nutrition/metabolism, immune-related, physical fitness-related, and gut microbiome features.

Because of the difference in sex-specific effects, the groups were divided into male and female. The investigators then developed an aging-rate index that could be used to correlate different bodily systems with each other. Based on their findings, they classified the volunteers either as aging faster or aging slower than their chronological age.

Overall, they discovered that biological ages of different organs and systems had diverse correlations, and not all were expected. Although healthy weight and high physical fitness levels were expected to have a positive impact, the investigators were surprised by other findings. For example, having a more diverse gut microbiota indicated a younger gut while at the same time having a negative impact on the aging of the kidneys, possibly because the diversity of species causes the kidneys to do more work.

The investigators also used their approach to look at other datasets, including the National Health and Nutrition Examination Survey from the US Center for Disease Control and Prevention and the Chinese Longitudinal Healthy Longevity Survey, which includes data on more than 2,000 centenarians with matched middle-aged controls. In addition, they looked at single nucleotide polymorphisms (SNPs) to determine whether differences could be explained by genetic factors. There, they did find certain pathways that could be associated with aging rates.

The researchers plan to regularly follow up with the study participants to track the development of aging and validate their findings. Future studies will use additional approaches for classifying features of aging and studying the interactions between organ systems.

They also plan to use single-cell technology to look at programmed aging in more detail. “It’s important to capture the cell-to-cell variation in an aging individual, as this will tell us important information about the heterogeneity within cell types and tissues and provide important insights into aging mechanisms,” says co-corresponding author Claudio Franceschi of Lobachevsky State University in Russia.

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The impacts from using genetic testing to track down relatives

Source: Cell Press
Date: 2/24/2022
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Genetic genealogy has become a popular hobby over the past several years, thanks to direct-to-consumer (DTC) genetic testing and relative-finder services offered by some DTC genetic testing companies. In a paper published February 24 in the American Journal of Human Genetics, researchers report results from a survey that asked people who had participated in these services what effect the discovery of previously unknown relatives had on their lives.

Among the most important findings were that identifying a genetic relative appeared to be somewhat common. Additionally, those discoveries were generally experienced as neutral or positive and didn’t appear to have a big impact on participants’ lives. However, some participants learned things that could be considered significant and destabilizing — such as that their biological parent wasn’t who they thought. These participants were especially vulnerable to negative outcomes.

“Everyone on our team is involved in studying the ethical, legal, and social implications of DTC genetic testing, and we’ve been paying attention to stories in the media about individuals who’ve made surprising family discoveries from these tests and relative-matching services,” says lead author Christi Guerrini of the Center for Medical Ethics and Health Policy at Baylor College of Medicine. “We wanted to understand if these and other kinds of discoveries are common, how they’re experienced by those making the discoveries, and what people are doing as a result.”

The investigators sent the survey to about one million DTC genetic testing customers and genetic genealogy database participants; more than 26,000 responded. The final sample for analysis consisted of 23,196 completed or substantially completed surveys. Among the reasons that respondents said they chose to participate in this type of testing were to learn more about their family or build their family trees; to search for a biological parent, child, or other relative; or to investigate a suspicion that they might not be genetically related to family members.

“It seems that many — perhaps most — are just curious about their families and interested in building out their family trees, but it’s clear that quite a lot of participants are looking for someone or hoping to confirm something in particular,” Guerrini says. “It might be that they’re adopted and looking for a biological parent, or that they’ve always felt out of place in their family and want to see if there’s something to that feeling. Or they might be looking for information about a branch of their family tree that’s unknown to them, or to confirm a family story that’s been passed down over the years.”

Most respondents (82%) reported that they learned the identity of at least one genetic relative. Among this subpopulation, 10% identified a biological grandparent, 10% identified a full or half- sibling, and 7% identified a biological father. The survey asked whether the participant had chosen to contact any of their newly identified relatives and, if so, the reasons for doing so. It also asked whether their discoveries resulted in any life changes, including changes in health-related behaviors.

Guerrini says that the high number of people overall who identified an unknown genetic relative was not unexpected, because many of those relatives could be very distant ones. But she acknowledges that the high number of participants who found close relatives could be skewed by the type of people who choose to undergo relative matching in the first place. “Unfortunately, we can’t answer that question with our data, but I’m very interested in trying to do so in future research,” she says.

She adds that although these experiences appear to be interesting and enjoyable to a large number of people, it’s clear that some who are participating in these services have experienced negative outcomes. “In future research, we’d like to better understand those outcomes and what resources could be helpful in managing them,” she says.

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Research in mice identifies neurons that control locomotion

Source: Cell Press
Date: 1/20/2022
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For more than a century, scientists have known that while the commands that initiate movement come from the brain, the neurons that control locomotion once movement is underway reside within the spinal cord. In a study published January 20 in the journal Cell, researchers report that, in mice, they have identified one particular type of neuron that is both necessary and sufficient for regulating this type of movement. These neurons are called ventral spinocerebellar tract neurons (VSCTs).

“We hope that our findings will open up new avenues toward understanding how complex behaviors like locomotion come about and give us new insight into the mechanisms and biological principles that control this essential behavior,” says the paper’s senior author George Mentis, associate professor of pathology and cell biology in the Department of Neurology at Columbia University. “It’s also possible that our findings will lead to new ideas for therapeutic avenues, whether they involve treatments for spinal cord injury or neurodegenerative diseases that affect movement and motor control.”

VSCTs were discovered in the 1940s, but researchers have long believed that their main function was to relay messages about neuronal activity from the spinal cord to the cerebellum. The new study reports that instead they control locomotor behavior both during development and in adulthood.

“These findings were a huge surprise,” Mentis says. “One of the key discoveries in our study was that apart from their connection to the cerebellum, these neurons make connections with other spinal neurons that are also involved in locomotor behavior via their axon collaterals.”

The research involved several novel experimental approaches. One part of the research used optogenetics, employing LED light to regulate certain proteins that were expressed selectively in VSCTs to either activate or suppress the neuronal activity. Another set of experiments used chemogenetics, a process by which a chemical compound is used to activate or suppress synthetic ligands expressed artificially in these neurons, controlling their activity.

Leveraging the ability of intact spinal cords from newborn mice to function in a dish, the researchers showed that activation of VSCTs by light induced locomotor behavior. When VSCT activity was suppressed by light or by drugs, ongoing locomotor behavior was halted. During adulthood, freely moving mice stopped moving when the activity of VSCT was suppressed by injecting an inhibitory drug. Locomotor behavior was also tested by the ability of mice to swim. Mice were unable to swim and simply floated in the water when VSCTs were silenced. In all of these models and experiments, the researchers demonstrated that VSCTs alone were both necessary and sufficient for controlling locomotor activity — activating them was enough to induce activity while suppressing them was enough to stop it.

Mentis acknowledges that there are limitations to conducting this type of research in mice, including the fact that while humans are bipedal, mice are quadrupedal; thus, their locomotion could be regulated in a different way. But he notes that other research on neurodegenerative diseases and processes in mice has led to clinical trials in human patients, suggesting that these findings are also likely to be applicable.

For their next steps, the team plans to identify and map precisely the neuronal circuits that VSCTs make with motor neurons and other spinal neurons. They also would like to identify select genetic markers and uncover potential subpopulations of VSCTs and explore their role in different modes of locomotion. Finally, they plan to explore how the function of VSCTs is altered in the context of pathology and neurodegenerative diseases.

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A beetle chemical defense gland offers clues about how complex organs evolve

Source: Cell Press
Date: 12/9/2021
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Rove beetles are among the chemists of the insect world, concocting noxious compounds within their bodies that are weaponized to ward off predators, enabling the beetles to survive in leaf litter and soil in ecosystems across the planet. On December 9 in the journal Cell, investigators studying a species of rove beetle report how two distinct cell types have come together to form a specialized gland for making and secreting these defensive cocktails. The work has implications for mapping out the evolution of more sophisticated organs found across the animal kingdom, including in humans.

“These beetles are fantastic models for understanding how new kinds of ecological relationships emerge during evolution through changes at the molecular, cellular, and behavioral levels,” says senior author Joseph Parker (@Pselaphinae) of the California Institute of Technology. “As part of this question, we’re very interested in how rove beetles have pieced together these glandular structures in their abdomens, which are made of different cell types that work together. These structures are the embodiment of a major conundrum: how complex organs evolve that are often composed of many different cell types that appear to seamlessly cooperate with each other. How this cooperativity emerges during evolution is challenging to explain.”

Parker’s lab focuses on rove beetles in part because of their ability to carve out niches for themselves in many different ecosystems, from in the dirt to inside ant colonies. One way they’ve been able to survive in the presence of other insects, such as ants, is through glands in their abdomen that release a defensive chemical compound that triggers pain receptors. The beetles have a supremely flexible body and can smear these chemical cocktails directly onto predators to defend themselves.

The species of rove beetle that was the focus of this research, Dalotia coriaria, has what’s called a tergal gland in its abdomen that releases a cocktail made of two compound types: benzoquinones, which are highly toxic but solids on their own, and solvents, a fatty acid-derived blend of an alkane and three esters. The latter compounds by themselves are benign, but they weaponize the benzoquinones by dissolving them.

Parker’s group investigated the tergal gland and found two cell types that were engaged in a biosynthetic division of labor. “One cell type makes the benzoquinones and the other makes the solvents,” Parker says. “Both are needed to create a functional secretion that confers adaptive value.”

In the study, the investigators used single-cell transcriptomics of the beetles’ abdominal segments to uncover novel enzyme pathways that enable the creation of these substances in each cell type. They then used these findings to dig deeper, exploring how each cell type’s pathway was constructed from components that functioned in other more ancient cell types elsewhere in the beetle. “We were able to discover the biosynthetic pathways in each cell type and could then ask how these pathways were stitched together during evolution,” Parker notes.

Remarkably, one of the cell types — the solvent cells that make the alkane and esters — was found to be a hybrid of cells comprising the beetle’s exoskeleton and two ancient metabolic cell types that make and store lipids and produce pheromones. “The beetle has recruited a major gene expression program from these ancient metabolic cell types and installed it into a patch of cuticle, creating a gland,” Parker says.

Further experiments — including placing the beetles into battle arenas with ants — revealed that when either the solvent or benzoquinone pathway was knocked down, the beetles lost their defensive capabilities. This suggested that under natural selection, both cell types are needed to confer the beetles’ chemical defense system. The investigators also found that the compound made by the tergal gland has antimicrobial properties, further raising the adaptive value of the gland.

The authors think the gland evolved via coevolution between the two cell types. “The solvent cells created a niche for a second cell type to produce the solid benzoquinones, which could dissolve in the alkane and esters. A highly toxic secretion emerged that massively raised the gland’s adaptive value, locking the two cell types into a unit where they cooperate. In essence, a new organ emerged,” Parker says.

“Across the animal tree of life, you see complex multicellular organs that are composed of many different cell types functioning collectively,” Parker concludes. “Think of something like the mammalian eye, which has about 70 different cell types all functioning together to enable our visual system. The scenario we find playing out in the tergal gland — an organ made of only two cell types — you can imagine could go through further rounds as cell types create niches for new ones to be added, eventually generating really elaborate multicellular complexity.”

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Antihistamine drugs may improve outcomes for cancer patients receiving immunotherapy

Source: Cell Press
Date: 11/24/2021
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Since the first checkpoint inhibitor drugs were developed for the treatment of cancer about a decade ago, investigators have focused on ways to make them more effective. A study appearing November 24 in the journal Cancer Cell reports that the over-the-counter second-generation antihistamines appear to improve outcomes for cancer patients treated with anti-PD-1/PD-L1 therapies for a number of different types of cancer.

“We believe our findings could have implications for clinical practice if validated in prospective clinical studies,” says senior author Dihua Yu, a professor and chair ad interim of the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center. “For example, our study suggests that before immunotherapy treatment, testing patients’ plasma histamine level could help doctors decide whether patients may benefit from antihistamine treatment.”

The discovery was made after the investigators decided to look at the influence of 40 common medications on the efficacy of checkpoint inhibitors. These included over-the-counter drugs such as antacids and anti-inflammatories and prescription drugs such as antibiotics and steroids. When the researchers reviewed the patients’ electronic health records, they found that taking H1-antihistamines by patients receiving immunotherapy was significantly associated with improved overall survival.

Second-generation H1-antihistamines include cetirizine (Zyrtec), loratadine (Claritin), and, more recently, fexofenadine (Allegra). These drugs, which block metabolites called histamines released by immune cells, are widely used in cancer patients not only to relieve allergy symptoms but to prevent nausea and vomiting. However, the role of histamines has not previously been connected directly to cancer outcomes.

Meanwhile, the researchers noticed that some patients with “hot tumors”—those with high infiltration of cytotoxic T cells—who normally would be expected to respond well to immunotherapy still had very poor survival. To get an insight on what made these tumors different, they performed global gene expression analysis on patient samples.

“We found that histamine receptor 1 (HRH1) was identified as one of the top hits that show strong association with poor clinical outcome in hot tumors,” says co-first author Yi Xiao, an instructor of the Department of Molecular and Cellular Oncology and a member of Yu’s lab at MD Anderson.

Since H1-antihistamines specifically block histamine binding to HRH1, they connected the above findings back to the lab in mice. Their experiments revealed that cancer-secreted and allergic reaction-released histamines, as well as HRH1 high expression in macrophages, suppressed cytotoxic T cell activation and conferred resistance to immunotherapy, whereas antihistamines partially rescued all the phenotypes.

They also measured pretreatment plasma histamine levels in patients who were treated by anti-PD-1 immunotherapy. Corroborating their findings in mice, high histamine levels in patients were significantly correlated with worse responses to anti-PD-1 immunotherapy compared to patients with low levels of plasma histamine levels.

“We were surprised to find that almost all the cancer cells we tested have significantly increased secretion of histamines compared to normal cells,” Xiao says. “We know that allergy responses release a lot of histamines but didn’t expect such a stunning suppressive effect on antitumor immunity.”

One limitation of the research is that it focused solely on the function of macrophage-expressed HRH1 but not HRH1 in other immune and non-immune cell types. The researchers say it’s also possible that histamines may have a broader impact on the phenotype and activity of macrophages. That’s something they may explore in the future. 

They also note that it’s critical to choose the right antihistamines for cancer patients. This research indicated that only second-generation H1-antihistamines, which target HRH1 specifically, but not first-generation, non-selective H1-antihistamines led to improved outcomes.

“Tens of millions of people experience allergies every year. But how allergies impact cancer development and therapeutic response has not been well studied,” Yu says. “Our study just uncovered a tip of the iceberg, and we will continue to explore the relationship between the two diseases.”

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Many IVF embryos not implanted due to mosaic abnormalities may be viable

Source: Cell Press
Date: 11/18/2021
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One factor that limits the success of in vitro fertilization (IVF) procedures is the number of viable embryos available for implantation in the uterus. A study published November 18 in the American Journal of Human Genetics suggests that many of the embryos that are discarded or downgraded due to chromosomal abnormalities have the potential to lead to successful pregnancies. These findings could have important implications for people undergoing IVF treatments.

“We believe the clinical data generated from this trial will resolve some of the major concerns that arise during pre-implantation genetic testing and will be of fundamental importance for helping many infertile patients make more informed reproductive decisions,” says first author Antonio Capalbo (@antonio_capalbo), a specialist in reproductive genetics at Igenomix Italy, a company that provides genetic testing services. “This trial has the potential to drive a radical change in the clinical management of IVF and to support the development of updated guidelines and recommendation from scientific societies.”

The researchers focused on the prevalence and distribution of aneuploid cells (cells with chromosome imbalances) within lab-created blastocysts, the precursor to embryos. In particular, they looked at a condition called mosaicism, in which embryos have a mix of normal and aneuploid cells. Currently, fewer than 3% of these mosaic embryos are used in IVF treatments, and several clinics in the US do not allow them to be transferred. But in many blastocysts with this type of mosaicism, the area of abnormal cells is localized to a small area that may not affect development.

In the current study, investigators conducted a double-blinded trial in which patients undergoing IVF at five hospitals in Italy had their embryos tested with pre-implantation genetic testing that looked specifically for mosaic aneuploidy. In addition to euploid embryos (those with no aneuploidy), embryos with low-grade mosaicism (20%–30% aneuploid cells) and medium-grade mosaicism (30%–50% aneuploid cells) were blindly reported as euploid and implanted. The primary outcome of the trial was defined as live birth rate, and the secondary outcome was miscarriage rate.

“It was already known that putative mosaic embryos can develop to term and make healthy babies, but many of the previous studies that looked at this issue were affected by selection bias toward a population of patients that had a poor prognosis because they had previously failed implantations with euploid embryos,” he says. “Alternatively, mosaic embryos have been transferred into patients producing only aneuploid embryos, again introducing a strong selection bias toward a poor-prognosis population.”

The researchers say the current study avoided that bias by being a non-selection trial, in which any embryos that fit the defined criteria were eligible for transfer. Overall, they found that across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos, the rates of live births and miscarriages were similar. The obstetrical and neonatal outcomes were also similar.

“We did this study because we were concerned about the unmotivated dismissal of putative mosaic embryos from clinical use without robust data to support this practice,” Capalbo says. “Our findings suggest that reporting mosaicism as it is currently performed doesn’t provide any element of clinical utility for IVF patients. Accordingly, it seems reasonable these genetic findings not be reported after pre-implantation genetic testing, similar to what is done for variants of unknown significance in clinical genetic testing. If these findings are reported, patients should be aware that the embryos are otherwise healthy and normal.”

The investigators expect that this study will immediately impact clinical practice, driving an update of guidelines and recommendations from relevant scientific societies and allowing IVF patients to improve their decision-making process when evaluating the transfer of mosaic embryos. “In the future, we encourage the preliminary use of data from non-selection trials before incorporating new pre-implantation genetic testing algorithms and aneuploidy classification criteria in routine practice,” Capalbo says.

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Gut microbiota differences seen in people with autism may be due to dietary preferences

Source: Cell Press
Date: 11/11/2021
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Research suggested that autism spectrum disorder (ASD) may be at least partly caused by differences in the composition of the gut microbiota, based on the observation that certain types of microbes are more common in people with autism. But a paper appearing November 11 in the journal Cell suggests that the link may actually work the other way around: the diversity in species found in the guts of children with autism may be due to their restricted dietary preferences associated with autism, rather than the cause of their symptoms.

“There’s a lot of interest surrounding the role of the gut microbiome in autism, but not a lot of hard evidence,” says senior author Jacob Gratten, of Mater Research in partnership with The University of Queensland in Brisbane, Australia. “Our study, which is the largest to date, was designed to overcome some of the limitations of prior work.”

Over the past decade, as next-generation sequencing of the microbial species in the gut has made analysis of the microbiome more automated and less-time consuming, a number of studies have examined the link between particular species of microbes in the gut and mental health. The gut-brain axis has been linked not only to ASD but also to anxiety, depression, and schizophrenia. The possibility of targeting the microbiota is a growing area of research for new treatments.

In the Cell study, the investigators analyzed stool samples from a total of 247 children between the ages of 2 and 17. The samples were collected from 99 children diagnosed with ASD, 51 paired undiagnosed siblings, and 97 unrelated, undiagnosed children. The subjects included in the analysis were from the Australian Autism Biobank and Queensland Twin Adolescent Brain Project.

The investigators analyzed the samples by metagenomic sequencing, which looks at the entire genome of microbial species rather than short genetic barcodes (as with 16S analysis). It also provides gene-level information rather than just species-level information, and provides a more accurate representation of microbiome composition than 16S analysis, a technique used in many of the earlier studies linking the microbiome to autism.

“We also carefully accounted for diet in all our analyses, along with age and sex,” says first author Chloe Yap, an MD-PhD student who works with Gratten. “The microbiome is strongly affected by the environment, which is why we designed our study with two comparison groups.”

Based on their analysis, the researchers found limited evidence for a direct association of autism with the microbiome. However, they did find a highly significant association of autism with diet and that an autism diagnosis was associated with less-diverse diet and poorer dietary quality. Moreover, psychometric measures of degree of autistic traits (including restricted interests, social communication difficulties, and sensory sensitivity) and polygenic scores (representing a genetic proxy) for ASD and impulsive/compulsive/repetitive behaviors were also related to a less-diverse diet.

“Taken together, the data support a strikingly simple and intuitive model, whereby autism-related traits promote restricted dietary preferences,” Yap says. “This in turn leads to lower microbiome diversity and more diarrhea-like stool.”

The researchers acknowledge several limitations to the current work. One is that the design of the study can’t rule out microbiome contributions prior to ASD diagnosis, nor the possibility that diet-related changes in the microbiome have a feedback effect on behavior. Another is that they could only account for the possible effect of antibiotics on the microbiome by excluding those taking these medications at the time of stool collection. Finally, no comparable datasets are currently available to confirm the findings.

“We hope that our findings encourage others in the autism research community to routinely collect metadata in “omics” studies to account for important (but often underappreciated) potential confounders such as diet,” Gratten says. “Our results also put the spotlight on nutrition for children diagnosed with autism, which is a clinically important (but underrecognized) contributor to overall health and wellbeing.”

The researchers plan to generate new data in a larger sample to replicate their findings.

The authors acknowledge the financial support of the Cooperative Research Centre for Living with Autism (Autism CRC), established and supported under the Australian Government’s Cooperative Research Centres Program. Additional funding support was provided by the Australian National Health and Medical Research Council, the Australian Research Council, and the University of Queensland.