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Researchers call for a focus on fitness over weight loss for obesity-related health conditions

Source: Cell Press
Date: 9/20/2021
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The prevalence of obesity around the world has tripled over the past 40 years, and, along with that rise, dieting and attempts to lose weight also have soared. But according to a review article publishing September 20 in the journal iScience, when it comes to getting healthy and reducing mortality risk, increasing physical activity and improving fitness appear to be superior to weight loss. The authors say that employing a weight-neutral approach to the treatment of obesity-related health conditions also reduces the health risks associated with yo-yo dieting.

“We would like people to know that fat can be fit, and that fit and healthy bodies come in all shapes and sizes,” says co-author Glenn Gaesser of the College of Health Solutions at Arizona State University. “We realize that in a weight-obsessed culture, it may be challenging for programs that are not focused on weight loss to gain traction. We’re not necessarily against weight loss; we just think that it shouldn’t be the primary criterion for judging the success of a lifestyle intervention program.”

“This is especially important when you consider the physiological realities of obesity,” says co-author Siddhartha Angadi of the School of Education and Human Development at the University of Virginia. “Body weight is a highly heritable trait, and weight loss is associated with substantial metabolic alterations that ultimately thwart weight loss maintenance.”

Obesity is associated with a number of health conditions, including cardiovascular disease, diabetes, cancer, and problems with the bones and joints. But weight cycling, commonly called yo-yo dieting, is also associated with health problems, including muscle loss, fatty liver disease, and diabetes. The authors say that by focusing on fitness rather than weight loss, people can gain the benefits of exercise while avoiding the risks associated with weight cycling.

Current public health guidelines recommend that adults accumulate 150-300 minutes per week of moderate-intensity physical activity (the intensity equivalent to walking at casual-to-brisk pace) or 75-150 minutes per week of vigorous-intensity physical activity (the intensity equivalent to jogging or running). “But it’s important to note that the benefits of exercise are dose dependent, with the biggest benefits coming from just moving out of the couch-potato zone to doing at least some moderate-intensity activity,” Gaesser says. “It’s also important to emphasize that physical activity can be accumulated throughout the day. For example, multiple short walks during the day (even as short as two to ten minutes each) are just as beneficial as one long walk for health benefits.”

In the review, the authors cite recent research focused on the magnitude of mortality risk reduction associated with weight loss compared to that associated with an increase in physical activity or cardiorespiratory fitness. The risk reduction associated with increasing fitness and physical activity was consistently greater than that associated with intentional weight loss. They also looked at the magnitude of reduction in the risk markers of cardiovascular disease that are associated with either weight loss or increased physical activity. They used meta-analyses from several studies done over a range of time periods and across a broad geographical area. “Science has generally supported the main points proposed in Big Fat Lies, a book on this topic that I first published in 1996,” Gaesser notes.

The researchers acknowledge limitations in the existing body of research, including the fact that this field is heavily reliant on epidemiological studies that do not definitively establish cause and effect, and note that only large, randomized, controlled clinical trials can fully examine the outcomes of using a fitness-focused approach to optimize cardiometabolic mortality risk in people who are obese. “Collectively, however, these epidemiological studies demonstrate strong and consistent associations, and this is why meta-analyses can be useful,” Angadi says. “In the case of physical activity and fitness, the epidemiological evidence is supported by a large body of experimental studies and randomized controlled trials that have established plausible mechanisms for the consistent findings in epidemiological studies.”

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People synchronize heart rates while listening attentively to stories

Source: Cell Press
Date: 9/14/2021
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People often unconsciously synchronize bodily functions like heartbeat and breathing when they share an experience, such as a live performance or have a personal conversation. According to a new study, subjects’ heart rates synchronize even if they are just listening to a story by themselves, and this synchronization only occurs when the subjects are paying attention to the story. The findings from the research are reported September 14 in the journal Cell Reports.

“There’s a lot of literature demonstrating that people synchronize their physiology with each other. But the premise is that somehow you’re interacting and physically present the same place,” says co-senior author Lucas Parra, a professor at City College of New York. “What we have found is that the phenomenon is much broader, and that simply following a story and processing stimulus will cause similar fluctuations in people’s heart rates. It’s the cognitive function that drives your heart rate up or down.”

“What’s important is that the listener is paying attention to the actions in the story,” adds co-senior author Jacobo Sitt (@jdsitt), a researcher at the Paris Brain Institute and Inserm. “It’s not about emotions, but about being engaged and attentive, and thinking about what will happen next. Your heart responds to those signals from the brain.”

The investigators conducted a series of four experiments to explore the role of consciousness and attention in synchronizing participants’ heart rates. In the first, healthy volunteers listened to an audiobook of Jules Verne’s 20,000 Leagues Under the Sea. As they listened, their heart rate changed based on what was happening in the story, as measured by electrocardiogram (EKG). The researchers found that the majority of subjects showed increases and decreases in their heart rate at the same points in the narrative.

In the second experiment, volunteers watched short instructional videos. Because the videos were educational with no underlying emotional variations, this experiment confirmed that emotional engagement in a story was not playing a part. The first time they watched the videos, heart rates across the subjects showed similar fluctuations. The participants then watched the videos a second time while counting backwards in their heads. That time, the lack of attention resulted in a drop in the synchronization of heart rates across subjects, confirming that attention was important.

In the third experiment, the subjects listened to short children’s stories, some while attentive and others while being distracted, and then were asked to recall facts from the stories. The researchers found that the fluctuations seen in the participants’ heart rates were predictive of how well they did at answering questions about the story—more synchronization predicted better test scores. This indicated that changes in heart rate were a signal of conscious processing of the narrative.

When the researchers looked at changes in breathing rates, they didn’t see the same synchronization among the subjects. This was surprising, since breathing is known to affect heart rate.

The fourth experiment was similar to the first, but it included both healthy volunteers and patients with disorders of consciousness—such as those in comas or persistent vegetative states. All subjects were presented with an audiobook of a children’s story. As expected, the patients had lower rates of heart synchronization than did healthy controls. When the patients were examined six months later, some of them with higher synchronization had regained some consciousness.

“This study is still very preliminary, but you can imagine this being an easy test that could be implemented to measure brain function,” Sitt says. “It doesn’t require a lot of equipment. It even could be performed in an ambulance on the way to the hospital.” He notes that much more validation is needed with larger numbers of patients as well as comparisons to accepted tests of brain function like EEGs and fMRIs. This is something his group is continuing to study.

Parra says such research is also important for understanding mindfulness and the brain-body connection. “Neuroscience is opening up in terms of thinking of the brain as part of an actual anatomical, physical body,” he says. “This research is a step in the direction of looking at the brain-body connection more broadly, in terms of how the brain affects the body.”

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Study confirms safety and effectiveness of COVID-19 vaccination in people with cancer

Source: Cell Press
Date: 6/10/2021
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Since the early days of the COVID-19 pandemic, there were questions about how people in active cancer treatment would fare if they became infected with SARS-CoV-2. The worries were due, in large part, to the effects that cancer and its treatments can have on the immune system. Now that COVID-19 vaccines are widely available, concerns have shifted to the safety and effectiveness of vaccination in this potentially vulnerable population. A study published June 5 in the journal Cancer Cell aims to allay those fears.

In a review of 200 patients with a wide spectrum of cancer diagnoses, researchers at Montefiore Health System and Albert Einstein College of Medicine in the Bronx, NY, found that after full vaccination, 94% of patients overall demonstrated seroconversion, which was determined by the presence of antibodies to the SARS-CoV-2 spike protein. Response rates were very high among patients with solid tumors and were lower in people with certain blood cancers, but even the majority of those patients mounted an immune response.

“Studies from early in the pandemic found that cancer patients who get COVID-19 have higher rates of morbidity and mortality compared to the general population,” says senior co-author Amit Verma, director of the Division of Hemato-Oncology at Montefiore and professor of medicine and of developmental and molecular biology at Einstein, and associate director, translational science, Albert Einstein Cancer Center. “We really need efforts to protect these vulnerable patients from infection. This study should help people feel reassured that these vaccines work very well, even in those receiving chemotherapy or immunotherapy.”

“This study confirms that there is no need for patients to wait for vaccination until they finish their chemotherapy or immunotherapy,” says senior co-author Balazs Halmos (@DrSteveMartin), director of the Multidisciplinary Thoracic Oncology Program at Montefiore, professor of medicine at Albert Einstein College of Medicine, and a member of the Albert Einstein Cancer Center (AECC). “The side effects from vaccination seen in these populations were not substantially worse than in other groups. Not a single patient had to go to the emergency room or be admitted to the hospital because of side effects from the vaccines.”

This study was the largest of its kind to look at seroconversion rates in cancer patients who have been fully vaccinated. Previous studies have looked at much smaller populations or have analyzed antibody levels after only the first dose of two-dose vaccines.

In serum tests to look for IgG levels after vaccination, the researchers found that among patients with solid tumors, 98% showed seroconversion. Among patients with hematologic cancers, the rate of seroconversion was 85%.

Patients receiving some treatments fared worse than others. Those receiving therapies for blood cancers that work by killing B cells (such as rituximab or CAR T therapies) had seroconversion rates of 70%. For those who had recently had bone marrow or stem cell transplants, the rate was 74%. But those rates were still much higher than expected, the researchers say.

“Although those receiving treatments that affect B cells didn’t do as well, patients with blood cancers that affect the myeloid cells rather than the lymphoid cells had a pretty good response with regard to seropositivity,” says first author Astha Thakkar (@asthakkar15) a Montefiore hematologic oncology fellow. “This includes people with acute myeloid leukemia and myelodysplastic syndrome.”

The researchers say that one reason their data are so significant is that they include patients who had a broad range of cancers and who were undergoing a number of different treatments. “The patients themselves were also diverse and were representative of the patients we treat in the Bronx,” Halmos says. “About one-third were Black and 40% were Hispanic.”

“Vaccination among these populations have been lower, even though these groups were hardest hit by the pandemic,” Verma concludes. “It’s important to stress how well these patient populations did with the vaccines.”

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A call for global oversight of unproven stem cell therapies

Source: Cell Press
Date: 6/8/2021
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The promotion and marketing of unproven stem cell therapies is a global problem that needs a global solution, say experts in a perspective published June 8 in the journal Stem Cell Reports. The authors of the paper call for the World Health Organization (WHO) to establish an advisory committee on regenerative medicine to tackle this issue and provide guidance for countries around the world.

“The field of regenerative medicine, which entails the manipulation of cells and tissues to obtain therapeutic properties, has been hailed as the most promising research field in modern medicine,” says senior author Mohamed Abou-el-Enein, the executive director of the joint University of Southern California/Children’s Hospital of Los Angeles Cell Therapy Program. “Starting in the early 2000s, however, unregulated stem cell clinics offering untested and poorly characterized treatments with insufficient information on their safety and efficacy began emerging all over the world, taking advantage of the media hype around stem cells and patients’ hope and desperation.”

“Advancing regenerative medicine is key to addressing the chronic disease burden, which the WHO considers to be a top international priority,” says first author Zubin Master, an associate professor of biomedical ethics at the Mayo Clinic. “And even though we have had significant advancement in the field of regenerative medicine, more needs to be done to ensure the safe and timely delivery of evidence-based interventions to patients, many of whom have exhausted all available options.”

The three authors of the commentary are Lawrence Goldstein Science Policy Fellows for the International Society for Stem Cell Research (ISSCR) and ex-officio members of ISSCR’s Public Policy Committee. They decided to write it after realizing that the majority of efforts in this space have focused on the marketing practices of providers and clinics, with much less focus on the tightening of regulations and enforcement to deal with the issue from a global standpoint.

The commentary highlights several proposals, including the harmonization of regulatory definitions surrounding stem cell and regenerative medicine and the importance of balancing the scientific evidence demonstrating safety and efficacy of stem cell and regenerative products with the needs of the patient.

“Many patients with chronic diseases who desire a regenerative medicine option have exhausted conventional medicine treatments and have no other suitable option,” Master says. “We should aim to develop pathways to provide patients with evidenced-based experimental regenerative intervention as possible options where there is oversight, especially in circumstances where there is no suitable alternative left.”

The authors write that the WHO, which already has established an expert advisory committee to develop global standards for governance and oversight of human genome editing, could initiate a similar committee to address the spread of unproven stem cell treatments. They say that the committee could promote greater harmonization among regulatory standards, convince member nations to prioritize this issue on their public health agendas, and develop educational and outreach tools that could help increase awareness among physicians and patients on the danger of this practice.

“I believe that the global spread of unproven stem cell therapies reflects critical gaps in the international system for responding to health crises, which could put the life of thousands of patients in danger,” Abou-el-Enein says. “Urgent measures are needed to enhance the global regulatory capacity to detect and respond to this eminent crisis rapidly.”

The authors also propose the establishment of an active surveillance mechanism to collect and analyze information on dubious clinics performing these procedures and share it with the public to increase awareness, as well as taking the appropriate legal actions. They note the importance of educational programs for patients and physicians on the realistic potential of stem cells and the regulatory pathways that are in place for developing these promising therapies.

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Disabled researcher calls for better support for faculty

Source: Cell Press
Date: 5/18/2021
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Academic institutions need to do much more to support faculty members with disabilities and to create an environment in which they can thrive, argues a commentary published May 18 in the journal Trends in Neurosciences. The paper was written by Justin Yerbury, a cell and molecular neurobiologist who has amyotrophic lateral sclerosis (ALS), and his wife, Rachel Yerbury, a research psychologist.

“We want people to understand how tough life is for people with a disability,” says Justin Yerbury (@jjyerbury), a professor at the University of Wollongong in Australia. “When you add academia on top of that, it’s just incredible that disabled academics like me can actually continue to contribute in the way that we do.”

He uses a wheelchair, is unable to speak, and types by using eye movement, which means that typing a document takes him about ten times as long as it does for someone who types using their hands or voice commands. His research is focused on the molecular processes that underpin ALS, a disease that has affected many members of his family.

The commentary discusses how several aspects of academia create barriers for disabled investigators. Many of these obstacles are driven by high demands for bringing in grant money and producing frequent research publications. These challenges, which result in reduced funding when they are not met, in turn make it difficult to retain staff. This creates a cycle in which it’s very difficult for disabled academics to perform their jobs and carry out their research.

The authors note that visible disabilities, such as the one that Justin Yerbury has, as well as invisible disabilities, such as those people with most mental health disorders or people with autism who have typical functioning in most cognitive domains have, need to be taken into account when one considers constraints that make it difficult for people to compete at the academic level. They say that underrepresentation of people with disabilities in academia is not related to lack of interest on the part of people who might choose to enter the field but to the difficulties created by the high expectations of the profession.

In the commentary, the Yerburys point out that although universities offer accommodations and adjustments for disabled students, they don’t extend the same measures to faculty. “Perhaps it’s easier for universities to make adjustments for students, or perhaps it’s expected that if you get to the academic level, you can compete, cope, and flourish regardless,” says Rachel Yerbury, who is a research psychologist at the University of Wollongong and studies how nature affects mental health and well-being. She adds that universities might support students with disabilities because they don’t want to risk discrimination claims.

The Yerburys highlight several ways in which academia could improve. These changes include leveling the playing field and focusing on equity rather than equality; reducing the pressure to compete for all academics, which makes the field almost impossible for disabled academics and dissuades them from entering it in the first place; and challenging ableism in the academy. “Ableism, or the expectations of being able-bodied or able-minded, can be subtle and underhanded,” Rachel Yerbury says. “Many academics and institutions may not even realize that they labor under these assumptions.”

She adds that this problem is not unique to academia either. “I think most industries have a long way to go in terms of discrimination and ableism.”

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Global study of 60 cities’ microbes finds each has a signature microbial fingerprint

Source: Cell Press
Date: 5/26/2021
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An international consortium has reported the largest-ever global metagenomic study of urban microbiomes, spanning both the air and the surfaces of multiple cities. The international project, which sequenced and analyzed samples collected from public transit systems and hospitals in 60 cities around the world, features comprehensive analysis and annotation for all the microbial species identified—including thousands of viruses and bacteria and two archaea not found in reference databases. The study appears May 26 in the journal Cell.

“Every city has its own ‘molecular echo’ of the microbes that define it,” says senior author Christopher Mason, a professor at Weill Cornell Medicine (WCM) and the director of the WorldQuant Initiative for Quantitative Prediction. “If you gave me your shoe, I could tell you with about 90% accuracy the city in the world from which you came.”

The findings are based on 4,728 samples from cities on six continents taken over the course of three years, characterize regional antimicrobial resistance markers, and represent the first systematic worldwide catalogue of the urban microbial ecosystem. In addition to distinct microbial signatures in various cities, the analysis revealed a core set of 31 species that were found in 97% of samples across the sampled urban areas. The researchers identified 4,246 known species of urban microorganisms, but they also found that any subsequent sampling will still likely continue to find species that have never been seen before, which highlights the raw potential for discoveries related to microbial diversity and biological functions awaiting in urban environments.

This project began in 2013, when Mason started collecting and analyzing microbial samples in the New York City subway system. After he published his first findings, he was contacted by researchers from all over the world who wanted to do similar studies in their own cities. He developed a protocol for collecting the samples and posted an instructional video on YouTube. The samples were collected with DNA- and RNA-free swabs and sent to a lab at WCM for analysis, along with positive and negative controls. Much of the analysis and assemblage of sequences is done on an Extreme Science and Engineering Discovery Environment (XSEDE) supercomputer in Pittsburgh, which led to the discovery of 10,928 viruses and 748 bacteria that are not present in any reference databases.

The worldwide interest inspired Mason in 2015 to create the International MetaSUB Consortium (short for Metagenomics and Metadesign of Subways and Urban Biomes), which has since expanded to collecting samples from air, water, and sewage in addition to hard surfaces. The group oversees projects such as Global City Sampling Day (gCSD), held every year on June 21, and has done wide-ranging studies including a comprehensive microbial analysis of Rio de Janeiro’s city surfaces and its mosquitoes before, during, and after the 2016 Summer Olympics. Another project, launched in 2020, is focused on investigating the prevalence of SARS-CoV-2 and other coronaviruses in domestic cats, and a project also is planned for the 2021 Tokyo Olympics.

The new research has implications for detecting outbreaks of both known and unknown infections and for studying the prevalence of antibiotic resistant microbes in different urban environments. It also can contribute to new discoveries about the evolution of microbial life. MetaSUB researchers in Switzerland (Andre Kahles and Gunnar Rätsch) also released a searchable, global DNA sequence portal (MetaGraph, https://metagraph.ethz.ch/search) that indexed all known genetic sequences (including MetaSUB data), which maps any known or newly discovered genetic elements to their location on Earth and can aid in the discovery of new microbial interactions and putative functions.

“There are millions of species on Earth, but we have a complete, solid genome reference for only 100,000 to 200,000 at this point,” Mason says, explaining that the discovery of new species can help with the building of microbial family trees to see how different species are related to one another.

The findings also have many potential practical applications. “Based on the sequence data that we’ve collected so far, we’ve already found more than 800,000 new CRISPR arrays,” he says. Additionally, the findings indicate the presence of new antibiotics and small molecules annotated from biosynthetic gene clusters (BGCs) that have promise for drug development.

“One of the next steps is to synthesize and validate some of these molecules and predicted BGCs, and then see what they do medically or therapeutically,” Mason says. “People often think a rainforest is a bounty of biodiversity and new molecules for therapies, but the same is true of a subway railing or bench.”

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Researchers identify a psychedelic-like drug without the hallucinogenic side effects

Source: Cell Press
Date: 4/28/2021
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Psychedelic drugs have shown promise for treating neuropsychiatric disorders such as depression and posttraumatic stress disorder. However, due to their hallucinatory side effects, some researchers are trying to identify drugs that could offer the benefits of psychedelics without causing hallucinations. In the journal Cell on April 28, researchers report they have identified one such drug through the development of a genetically encoded fluorescent sensor–called psychLight–that can screen for hallucinogenic potential by indicating when a compound activates the serotonin 2A receptor.

“Serotonin reuptake inhibitors have long been used for treating depression, but we don’t know much about their mechanism. It’s like a black box,” says senior author Lin Tian (@LinTianLab), an associate professor in the Department of Biochemistry and Molecular Medicine in the School of Medicine at the University of California, Davis. “This sensor allows us to image serotonin dynamics in real time when animals learn or are stressed and visualize the interaction between the compound of interest and the receptor in real time.”

Tian’s lab joined forces with the lab of David E. Olson, an assistant professor in the Department of Chemistry at UC Davis, whose lab is focused on drug discovery. “This paper was an exceptionally collaborative effort,” says Olson, a co-author on the study. “My lab is really interested in the serotonin 2A receptor, which is the target of both psychedelic drugs and classic antipsychotics. Lin’s lab is a leader in developing sensors for neuromodulators like serotonin. It just made perfect sense for us to tackle this problem together.”

Experts believe that one of the benefits of using psychedelic drugs over existing drugs is that they appear to promote neural plasticity–essentially allowing the brain to rewire itself. If proven effective, this approach could lead to a drug that works in a single dose or a small number of doses, rather than having to be taken indefinitely. But one thing that researchers don’t know is whether patients would be able to gain the full benefit of neural plasticity without undergoing the “psychedelic trip” part of the treatment.

In the paper, the investigators report that they used psychLight to identify a compound called AAZ-A-154, a previously unstudied molecule that has the potential to act on beneficial pathways in the brain without hallucinogenic effects. “One of the problems with psychedelic therapies is that they require close guidance and supervision from a medical team,” Olson says. “A drug that doesn’t cause hallucinations could be taken at home.”

The serotonin 2A receptor, also known as 5-HT2AR, belongs to a class of receptors called G protein-coupled receptors (GPCRs). “More than one-third of all FDA-approved drugs target GPCRs, so this sensor technology has broad implications for drug development,” Tian says. “The special funding mechanisms of BRAIN Initiative from the National Institutes of Health allowed us to take a risky and radical approach to developing this technology, which could open the door to discovering better drugs without side effects and studying neurochemical signaling in the brain.”

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A psychologist’s guide to donating more effectively to charities

Source: Cell Press
Date: 4/29/2021
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The decision to donate to a charity is often driven by emotion rather than by calculated assessments based on how to make the biggest impact. In a review article published on April 29 in the journal Trends in Cognitive Sciences, researchers look at what they call “the psychology of (in)effective altruism” and how people can be encouraged to direct their charitable contributions in ways that allow them to get more bang for the buck — and help them to have a larger influence.

“In the past, most behavioral science research that’s looked at charitable giving has focused on quantity and how people might be motivated to give more money to charity, or to give at all,” says first author Lucius Caviola (@LuciusCaviola), a postdoctoral researcher in the Department of Psychology at Harvard University. “Our paper focuses on the effectiveness of giving — how people decide which charity to give to and ways that people can be motivated to give to charities that are more effective.”

In the paper, the authors present a framework that distinguishes between motivation-based and knowledge-based influences on charitable giving. They note that although people often say they want to give effectively, they may be drawn to charities that are less effective and may not know how to determine which charities are more effective. The authors also discuss interventions that could encourage more effective altruism, such as providing more tangible details about a charity’s intervention strategies and how donors’ money is used.

Caviola believes that overhead ratios, which report what portion of donations goes to a charitable organization’s costs of operation versus its cause, and which many people focus on, are not the best way to measure a charity’s effectiveness. “These are completely different things, and I would argue that overhead ratio is irrelevant,” he says. “When someone does research before buying a car, they want to get the best car for their money, not the one where the company devoted the highest percentage of its profits directly to manufacturing costs.”

Instead, he says, more people should defer to experts that evaluate charities based on their effectiveness. “According to expert estimates, the most effective charities are often a hundred times more effective than typical charities,” the authors write. “A $100 donation can save a person in the developing world from trachoma, a disease that causes blindness. By contrast, it costs $50,000 to train a guide dog to help a blind person in the developed world. This large difference in impact per dollar is not unusual.” The authors cite the organization GiveWell as a reliable source of such information, based on its criteria designed to help donors do as much good as possible with every donation they make.

The authors acknowledge the importance of emotion in donating to charity and suggest that dividing donations between charities that are emotionally appealing and those that have the greatest impact can be an effective way to address both sides of this issue. “Research has shown that there are psychological conflicts between these two preferences,” Caviola says. “We have demonstrated that if you allow people to split their contributions, it can help them to resolve these conflicts.”

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Scientists generate human-monkey chimeric embryos

Source: Cell Press
Date: 4/15/2021
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Investigators in China and the United States have injected human stem cells into primate embryos and were able to grow chimeric embryos for a significant period of time — up to 20 days. The research, despite its ethical concerns, has the potential to provide new insights into developmental biology and evolution. It also has implications for developing new models of human biology and disease. The work appears April 15 in the journal Cell.

“As we are unable to conduct certain types of experiments in humans, it is essential that we have better models to more accurately study and understand human biology and disease,” says senior author Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory at the Salk Institute for Biological Sciences. “An important goal of experimental biology is the development of model systems that allow for the study of human diseases under in vivo conditions.”

Interspecies chimeras in mammals have been made since the 1970s, when they were generated in rodents and used to study early developmental processes. The advance that made the current study possible came last year when this study’s collaborating team — led by Weizhi Ji of Kunming University of Science and Technology in Yunnan, China — generated technology that allowed monkey embryos to stay alive and grow outside the body for an extended period of time.

In the current study, six days after the monkey embryos had been created, each one was injected with 25 human cells. The cells were from an induced pluripotent cell line known as extended pluripotent stem cells, which have the potential to contribute to both embryonic and extra-embryonic tissues. After one day, human cells were detected in 132 embryos. After 10 days, 103 of the chimeric embryos were still developing. Survival soon began declining, and by day 19, only three chimeras were still alive. Importantly, though, the percentage of human cells in the embryos remained high throughout the time they continued to grow.

“Historically, the generation of human-animal chimeras has suffered from low efficiency and integration of human cells into the host species,” Izpisua Belmonte says. “Generation of a chimera between human and non-human primate, a species more closely related to humans along the evolutionary timeline than all previously used species, will allow us to gain better insight into whether there are evolutionarily imposed barriers to chimera generation and if there are any means by which we can overcome them.”

The investigators performed transcriptome analysis on both the human and monkey cells from the embryos. “From these analyses, several communication pathways that were either novel or strengthened in the chimeric cells were identified,” Izpisua Belmonte explains. “Understanding which pathways are involved in chimeric cell communication will allow us to possibly enhance this communication and increase the efficiency of chimerism in a host species that’s more evolutionarily distant to humans.”

An important next step for this research is to evaluate in more detail all the molecular pathways that are involved in this interspecies communication, with the immediate goal of finding which pathways are vital to the developmental process. Longer term, the researchers hope to use the chimeras not only to study early human development and to model disease, but to develop new approaches for drug screening, as well as potentially generating transplantable cells, tissues, or organs.

An accompanying Preview in Cell outlines potential ethical considerations surrounding the generation of human/non-human primate chimeras. Izpisua Belmonte also notes that “it is our responsibility as scientists to conduct our research thoughtfully, following all the ethical, legal, and social guidelines in place.” He adds that before beginning this work, “ethical consultations and reviews were performed both at the institutional level and via outreach to non-affiliated bioethicists. This thorough and detailed process helped guide our experiments.”

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Ancient DNA reveals clues about how tuberculosis shaped the human immune system

Source: Cell Press
Date: 3/4/2021
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COVID-19 is only the latest infectious disease to have had an outsized impact on human life. A new study employing ancient human DNA reveals how tuberculosis has affected European populations over the past 2,000 years, specifically the impact that disease has had on the human genome. This work, which publishes March 4 in the American Journal of Human Genetics, has implications for studying not only evolutionary genetics, but also how genetics can influence the immune system.

“Present-day humans are the descendants of those who have survived many things — climate changes and big epidemics, including the Black Death, Spanish flu, and tuberculosis,” says senior author Lluis Quintana-Murci of the Institut Pasteur in France. “This work uses population genetics to dissect how natural selection has acted on our genomes.”

This research focused on a variant of the gene TYK2, called P1104A, which first author Gaspard Kerner had previously found to be associated with an increased risk of becoming ill after infection with Mycobacterium tuberculosis when the variant is homozygous. (TYK2 has been implicated in immune function through its effect on interferon signaling pathways.) Kerner, a PhD student studying genetic diseases at the Imagine Institute of Paris University, began collaborating with Quintana-Murci, an expert in evolutionary genomics, to study the genetic determinants of human tuberculosis in the context of evolution and natural selection.

Using a large dataset of more than 1,000 European ancient human genomes, the investigators found that the P1104A variant first emerged more than 30,000 years ago. Further analysis revealed that the frequency of the variant drastically decreased about 2,000 years ago, around the time that present-day forms of infectious Mycobacterium tuberculosis strains became prevalent. The variant is not associated with other infectious bacteria or viruses.

“If you carry two copies of this variant in your genome and you encounter Mycobacterium tuberculosis, you are very likely to become sick,” Kerner says. “During the Bronze Age, this variant was much more frequent, but we saw that it started to be negatively selected at a time that correlated with the start of the tuberculosis epidemic in Europe.”

“The beauty of this work is that we’re using a population genetics approach to reconstruct the history of an epidemic,” Quintana-Murci explains. “We can use these methods to try to understand which immune gene variants have increased the most over the last 10,000 years, indicating that they are the most beneficial, and which have decreased the most, due to negative selection.”

He adds that this type of research can be complementary to other types of immunology studies, such as those performed in the laboratory. Moreover, both researchers say these tools can be used to study the history and implications of many different genetic variants for multiple infectious diseases.