UT Southwestern scientists have identified key genes involved in brain waves that are pivotal for encoding memories. The findings, published online this week in Nature Neuroscience, could eventually be used to develop novel therapies for people with memory loss disorders such as Alzheimer’s disease and other forms of dementia.
Making a memory involves groups of brain cells firing cooperatively at various frequencies, a phenomenon known as neural oscillations. However, explain study leaders Bradley C. Lega, M.D., associate professor of neurological surgery, neurology, and psychiatry, and Genevieve Konopka, Ph.D., associate professor of neuroscience, the genetic basis of this process is not clear.
“There’s a famous saying for 100 years in neuroscience: Neurons that fire together will wire together,” says Lega. “We know that cells involved in learning fire in groups and form new connections because of the influence of these oscillations. But how genes regulate this process in people is completely unknown.”
Lega and Konopka, both members of the Peter O’Donnell Jr. Brain Institute, collaborated on a previous study to explore this question, collecting data on neural oscillations from volunteers and using statistical methods to connect this information to data on gene activity collected from postmortem brains. Although these results identified a promising list of genes, Konopka says, there was a significant shortcoming in the research: The oscillation and genetic data came from different sets of individuals.
More recently, the duo capitalized on an unprecedented opportunity — performing a similar study on patients undergoing surgeries in which damaged parts of their brains were removed to help control their epilepsy.
The researchers worked with 16 volunteers from UT Southwestern’s Epilepsy Monitoring Unit, where epilepsy patients stay for several days before having surgery to remove the damaged parts of their brains that spark seizures. Electrodes implanted in these patients’ brains over this time not only help their surgeons precisely identify the focus of the seizure, Lega says, but can also provide valuable information on the brain’s inner workings.

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While recording the electrical activity in the brains of 16 volunteers, the researchers had them do “free recall” tasks that involved reading a list of 12 words, doing a short math problem to distract them, and then recalling as many words as possible. As these patients were memorizing the word lists, their brain waves were recorded, creating a dataset that differed slightly from person to person.
About six weeks later, each volunteer underwent a temporal lobectomy — removal of the brain’s temporal lobe — to cure their seizures. This area frequently serves as an originator of epileptic seizures and is also important for memory formation. Within five minutes of the surgery, the damaged brain tissue was sent for processing to assess genetic activity.
Konopka’s team first performed whole RNA sequencing, a technique that identifies active genes, in temporal lobe samples that included all the brain’s cell types. Using statistical techniques that linked this activity to the patients’ neural oscillations during the free recall task, the researchers identified 300 genes that appeared to play a part in oscillatory activity. The researchers narrowed this number to a dozen “hub genes” that appeared to control separate gene networks.
Next, the researchers looked at the activity of these hub genes in separate cell types within the samples. Surprisingly, they found that several of these hubs weren’t active within nerve cells themselves but in a different population of cells known as glia. These cells provide support and protection for nerve cells, including manufacturing the fatty layer that insulates nerve cells so they can efficiently pass electrical signals.
Finally, the researchers used a technique called ATAC-seq, which identifies areas of DNA that are open for molecules called transcription factors to attach to and activate genes. Using this approach, they honed in on SMAD3, a gene that appears to serve as a master regulator to control activity of many of the hub genes and the genes they control in return.
Konopka and Lega note that several of the genes they identified as important in human neural oscillations have been linked to other disorders that can affect learning and memory, such as autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, and schizophrenia. With further research into these genes and the networks they operate within, it may eventually be possible to target select genes with pharmaceuticals to improve memory in individuals with these and other conditions, the researchers say.
“This gives us an entry point,” says Konopka, a Jon Heighten Scholar in Autism Research. “It’s something we can focus on to learn more about the underpinnings of human memory.”
This work was supported by the National Institute of Mental Health (F30MH105158 and MH103517), National Institute on Drug Abuse (5T32DA007290-25), National Heart, Lung, and Blood Institute (1T32HL139438-01A1); National Institute of Neurological Disorders and Stroke (NS106447 and NS107357), a UT BRAIN Initiative Seed Grant (366582), the Chilton Foundation, the National Center for Advancing Translational Sciences of the NIH under the Center for Translational Medicine’s award number UL1TR001105, The Chan Zuckerberg Initiative, an advised fund of Silicon Valley Community Foundation (HCA-A-1704-01747), and the James S. McDonnell Foundation 21st Century Science Initiative in Understanding Human Cognition — Scholar Award.

The mosquito protein AEG12 strongly inhibits the family of viruses that cause yellow fever, dengue, West Nile, and Zika and weakly inhibits coronaviruses, according to scientists at the National Institutes of Health (NIH) and their collaborators. The researchers found that AEG12 works by destabilizing the viral envelope, breaking its protective covering. Although the protein does not affect viruses that do not have an envelope, such as those that cause pink eye and bladder infections, the findings could lead to therapeutics against viruses that affect millions of people around the world. The research was published online in PNAS.
Scientists at the National Institute of Environmental Health Sciences (NIEHS), part of NIH, used X-ray crystallography to solve the structure of AEG12. Senior author Geoffrey Mueller, Ph.D., head of the NIEHS Nuclear Magnetic Resonance Group, said at the molecular level, AEG12 rips out the lipids, or the fat-like portions of the membrane that hold the virus together.
“It is as if AEG12 is hungry for the lipids that are in the virus membrane, so it gets rid of some of the lipids it has and exchanges them for the ones it really prefers,” Mueller said. “The protein has high affinity for viral lipids and steals them from the virus.”
As a result, Mueller says the AEG12 protein has great killing power over some viruses. While the researchers demonstrated that AEG12 was most effective against flaviviruses, the family of viruses to which Zika, West Nile, and others belong, it is possible AEG12 could be effective against SARS-CoV-2, the coronavirus that causes COVID-19. But, Mueller said it will take years of bioengineering to make AEG12 a viable therapy for COVID-19. Part of the problem is AEG12 also breaks opens red blood cells, so researchers will have to identify compounds that will make the protein target viruses only.
Alexander Foo, Ph.D., an NIEHS visiting fellow and lead author of the paper, explained that mosquitoes produce AEG12 when they take a blood meal or become infected with flaviviruses. Like humans, mosquitoes mount a vigorous immune response against these viruses, with AEG12 bursting their viral covering. But, at the beginning of the project, Foo and his colleagues knew little about the function of AEG12.
“The prospect of studying a new protein is exciting, yet daunting,” Foo said. “Thankfully, we had enough clues and access to a wide range of expertise at NIEHS to piece it together.”
Co-author and crystallography expert Lars Pedersen, Ph.D., is leader of the NIEHS Structure Function Group. He routinely uses information about a molecule’s physical makeup in his work and encourages more scientists to consider using this data in their studies. He said, “Our research shows that understanding the structure of a protein can be important in figuring out what it does and how it could help treat disease.”

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Materials provided by NIH/National Institute of Environmental Health Sciences. Note: Content may be edited for style and length.

How One Church is Vaccinating the NeighborhoodSimbarashe Cha for The New York TimesThe Rev. Dr. Calvin O. Butts III rolled his sleeve up last month as he got vaccinated in front of cameras to show that the coronavirus vaccine is safe. I spent the day with him as his church, Abyssinian Baptist, vaccinated others. Here is what else I saw →

SharecloseShare pageCopy linkAbout sharingimage copyrightGetty ImagesUK scientists have discovered a key inflammatory protein that rises in the blood of patients with severe Covid-19.The protein – known as GM-CSF – was found to be nearly 10 times higher in patients who went on to die from the virus. Scientists say that with further research, the protein could help identify those most at risk and provide clues for better targeted treatments for the disease. The work appears in Science Immunology.Researchers analysed blood samples from 470 patients admitted to hospital with Covid-19 in the UK, comparing them with samples from people with mild coronavirus, healthy people and stored samples from people who had previously had swine flu.They found several inflammatory proteins – part of the body’s immune response – were raised in people who were ill, but only GM-CSF was specific to severe Covid-19.Scientists are concerned that while some of these inflammatory proteins help the body fight off the illness, others may do more harm than good by damaging organs.Dr Kenneth Baillie, at the University of Edinburgh, said: “By studying patients with severe Covid-19 at large scale across the UK, we’re building a clearer picture of lung disease in Covid-19.”The lungs are being damaged by the patient’s own immune system rather than directly being damaged by the virus, and we can see specific signals in the immune system that might be responsible.”Researchers say further work will help them understand whether inflammatory proteins like GM-CSF are one of the factors driving severe disease, and whether dampening these proteins with specific drugs can help. Professor Peter Openshaw, of Imperial College London, said he hoped ultimately that the work would help find treatments that were more precise than some current therapies. He added: “The future that we all want to embrace is one in which instead of giving very broad acting, rather poorly understood immunosuppressive treatments like steroids, that we can actually begin to pinpoint some therapy that just takes out the specific pathway that is causing harm whilst allowing the rest of the immune system to continue to do its job of clearing out the virus and restoring health.”Several drugs that target GM-CSF are being trialled but none have yet been approved for use. OXFORD JAB: What is the Oxford-AstraZeneca vaccine?YOUR QUESTIONS: We answer your queriesVACCINE: When will I get the jab?COVID IMMUNITY: Can you catch it twice?LOCKDOWN TIPS: Five ways to stay positiveRelated Internet LinksISARIC4C consortium.websiteScience Immunology.websiteThe BBC is not responsible for the content of external sites.

Scientists and healthcare providers are beginning to use a new approach for assessing a person’s inherited risk for diseases like Type 2 diabetes, coronary heart disease and breast cancer, which involves calculating a polygenic risk score. The score provides an estimate of an individual’s risk for specific diseases, based on their DNA changes related to those diseases.
Despite the rise in studies using polygenic risk scores, researchers have observed inconsistencies in how such scores are calculated and reported. These differences threaten to compromise the adoption of polygenic risk scores in clinical care.
To address this concern, the research teams, funded primarily by the National Human Genome Research Institute (NHGRI), have published a 22-item framework in the journal Nature that identifies the minimal polygenic risk score-related information that scientists should include in their studies. This framework — created by NHGRI’s Clinical Genome Resource’s (ClinGen) Complex Disease Working Group and the Polygenic Score Catalog (PGS), an open database of polygenic risk scores — will help promote the validity, transparency and reproducibility of polygenic risk scores. NHGRI is part of the National Institutes of Health.
To calculate a person’s polygenic risk score, researchers survey DNA variants in over 6 billion locations in the human genome.
“A real challenge is that the research community has not adopted any universal best practices for reporting polygenic risk scores,” said Erin Ramos, Ph.D., a program director for ClinGen, deputy director of the NHGRI Division of Genomic Medicine and co-author of the paper. “With the field growing as fast as it is, we need standards in place so we can meaningfully evaluate these scores and determine which ones are ready to be used in clinical care.”
This framework builds off another best practice model called the Genetic Risk Prediction Studies (GRIPS) statement, published by an international working group in 2011. GRIPS placed an emphasis on models that included a smaller set of genomic variants and gene scores. However, genetic risk prediction models have evolved rapidly since then, and are based on a much larger set of genomic variants and more complex methodologies. Also, researchers have not fully adopted the GRIPS framework.
“A renewed emphasis on reporting standards by ClinGen and the Polygenic Score Catalog comes at a crucial time for polygenic risk scores,” said Genevieve Wojcik, Ph.D., M.H.S., an assistant professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, Baltimore, and corresponding author of the paper. “It specifies the minimum information that should be described in a research paper for interpreting a polygenic risk score, reproducing results and eventually translating the information into clinical care.”
Some of the new reporting framework items include detailing the study population and the basis for choosing that population.
“If we are to make these scores available to people around the world, the studies need to define who they are studying and why, in the clearest way possible,” said Katrina Goddard, Ph.D., director of Translational and Applied Genomics at the Kaiser Permanente Center for Health Research, Portland, Oregon, who also co-authored the paper. “Without that transparency and reproducibility, efforts to use polygenic risk scores may be undermined.”
The new framework suggests that scientists should explain the statistical methods they used to develop and validate the polygenic risk scores. Without a consistent way of reporting polygenic risk scores, it is nearly impossible to compare the utility of the scores for assessing disease risk in people. According to the new guidelines, researchers should also consider potential limitations of these scores and how clinicians should use the scores in patient care.
“If researchers can follow these guidelines, it will be more straightforward to evaluate published polygenic risk scores and decide which ones are a good fit for the clinical setting,” said Michael Inouye, Ph.D., director of the Cambridge Baker Systems Genomics Initiative, U.K., and co-senior author of the paper. “For diseases such as breast cancer and many others, we will be able to responsibly place patients in different risk categories and provide beneficial screening strategies and treatments. Ideally, in the future, we will detect risk early enough to combat the disease effectively.”

When we think about the causes of neurological disorders and how to treat them, we think about targeting the brain. But is this the best or only way? Maybe not. New research by scientists at Baylor College of Medicine suggests that microbes in the gut may contribute to certain symptoms associated with complex neurological disorders. The findings, published in the journal Cell, also suggest that microbe-inspired therapies may one day help to treat them.
Dr. Mauro Costa-Mattioli, professor and Cullen Foundation Endowed Chair in neuroscience and director of the Memory and Brain Research Center at Baylor, discovered with his team that different abnormal behaviors are interdependently regulated by the host’s genes and microbiome. Specifically, the team found that in mouse models for neurodevelopmental disorders, hyperactivity is controlled by the host’s genetics, whereas social behavior deficits are mediated by the gut microbiome.
More importantly from a therapeutic perspective, they found that treatment with a specific microbe that promotes the production of compounds in the biopterin family in the gut or treatment with a metabolically active biopterin molecule improved the social behavior but not motor activity.
“We are the bearers of both host and microbial genes. While most of the focus has traditionally been in host genes, the gut microbiome, the community of microorganisms that live within us, is another important source of genetic information,” Costa-Mattioli said.
The work by Costa-Mattioli’s group offers a different way of thinking about neurological disorders in which both human and microbial genes interact with each other and contribute to the condition. Their findings also suggest that effective treatments would likely need to be directed at both the brain and the gut to fully address all symptoms. Additionally, they open the possibility that other complex conditions, such as cancer, diabetes, viral infection or other neurological disorders may have a microbiome component.
Brain-gut-microbiome crosstalk
“It’s very difficult to study these complex interactions in humans, so in this study, we worked with a mouse model for neurodevelopmental disorders in which the animals lacked both copies of the Cntnap2 gene (Cntnap2-/- mice),” said co-first author Sean Dooling, a Ph.D. candidate in molecular and human genetics in the Costa-Mattioli lab. “These mice presented with social deficits and hyperactivity, similar to those observed in autism spectrum disorders (ASD). In addition, these mice, like many people with ASD, also had changes in the bacteria that make up their microbiome compared to the mice without the genetic change.”

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Further experiments showed that modulating the gut microbiome improved the social behavior in the mutant mice, but did not alter their hyperactivity, indicating that the changes in the microbiome selectively contribute to the animals’ social behavior.
“We were able to separate the contribution of the microbiome and that of the animal’s genetic mutation on the behavioral changes,” Dooling said. “This shows that the gut microbiome shouldn’t be ignored as an important variable in studying health and disease.”
Equipped with this knowledge, the researchers dug deeper into the mechanism underlying the microbiome’s effect on the animal’s social deficits. Based on their previous work, the investigators treated the mice with the probiotic microbe, L. reuteri.
“We found that L. reuteri also can restore normal social behavior but cannot correct the hyperactivity in Cntnap2-/- mice,” said co-first author Dr. Shelly Buffington, a former postdoctoral fellow in the Costa-Mattioli lab and now an assistant professor at the University of Texas Medical Branch in Galveston.
However, the bigger surprise came when the investigators administered to the asocial mice a metabolite or compound they found was increased in the host’s gut by L. reuteri. They discovered that the animals’ social deficits also were improved after treating them with the metabolite instead of the bacteria.

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“This provides us with at least two possible ways to modulate the brain from the gut, with the bacteria or the bacteria-induced metabolite,” said Buffington.
Bacteria to heal your brain & beyond
Could this work inspire new breakthroughs in treating neurological disorders? While it is still too early to say for sure, the investigators are particularly excited about the translational implications of their findings. “Our work strengthens an emerging concept of a new frontier for the development of safe and effective therapeutics that target the gut microbiome with selective probiotic strains of bacteria or bacteria-inspired pharmaceuticals,” Buffington said.
“As we learn more about how these bacteria work, we will be able to more precisely and effectively leverage their power to help treat the brain and perhaps more,” Dooling added.
This research represents important step forward in the field as many disorders, especially those affecting the brain, remain very difficult to treat.
“Despite all the scientific advances and the promise of gene manipulation, it is still difficult to modulate human genes to treat diseases, but modulating our microbiome may be an interesting, noninvasive alternative,” said Costa-Mattioli. Indeed, L. reuteri currently is being tested in a clinical trial in Italy in children with autism, and Costa-Mattioli aims to start his own trial soon.
“In my wildest dreams, I could have never imagined that microbes in the gut could modulate behavior and brain function. To think now that microbial-based strategies may be a viable way to treat neurological dysfunction, is still wild, but very exciting.”

On December 6, 2016, a high-energy particle hurtled to Earth from outer space at close to the speed of light. The particle, an electron antineutrino, smashed into an electron deep inside the ice sheet at the South Pole. This collision produced a particle that quickly decayed into a shower of secondary particles, triggering the sensors of the IceCube Neutrino Observatory, a massive telescope buried in the Antarctic glacier.
IceCube had seen a Glashow resonance event, a phenomenon predicted by Nobel laureate physicist Sheldon Glashow in 1960. With this detection, scientists provided another confirmation of the Standard Model of particle physics. It also further demonstrated the ability of IceCube, which detects nearly massless particles called neutrinos using thousands of sensors embedded in the Antarctic ice, to do fundamental physics. The result was published March 10 in Nature.
Sheldon Glashow first proposed this resonance in 1960 when he was a postdoctoral researcher at what is today the Niels Bohr Institute in Copenhagen, Denmark. There, he wrote a paper in which he predicted that an antineutrino — a neutrino’s antimatter twin — could interact with an electron to produce an as-yet undiscovered particle through a process known as resonance. The key was that the antineutrino had to have a precise energy to produce this resonance.
When the proposed particle, the W-minus boson, was finally discovered in 1983, it turned out to be much heavier than what Glashow and his colleagues had expected back in 1960. The Glashow resonance would require a neutrino with an energy of 6.3 petaelectronvolts, almost 1,000 times more energetic than what CERN’s Large Hadron Collider is capable of producing. No human-made particle accelerator on Earth, current or planned, can create a neutrino with that much energy.
Yet the enormous energies of supermassive black holes at the centers of galaxies and other extreme cosmic events can generate particles with energies impossible to create on Earth. Such a phenomenon was likely responsible for the antineutrino that reached IceCube in 2016, which smashed into Earth with an energy of 6.3 PeV — precisely as Glashow’s theory predicted.
“When Glashow was a postdoc at Niels Bohr, he could never have imagined that his unconventional proposal for producing the W-minus boson would be realized by an antineutrino from a faraway galaxy crashing into Antarctic ice,” says Francis Halzen, principal investigator of IceCube and professor of physics at the University of Wisconsin-Madison, the headquarters of IceCube maintenance and operations.

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Since IceCube started full operation in May 2011, the observatory has detected hundreds of high-energy astrophysical neutrinos and has produced a number of significant results in particle astrophysics, including the discovery of an astrophysical neutrino flux in 2013 and the first identification of a source of astrophysical neutrinos in 2018. The Glashow resonance event is noteworthy because of its extremely high energy. It is only the third event detected by IceCube with an energy greater than 5 PeV.
This result was a collaborative effort achieved by a team of three scientists: Lu Lu from Chiba University in Japan, now at UW-Madison, Tianlu Yuan from UW-Madison, and Christian Haack from RWTH Aachen University, now at TU Munich.
The Glashow resonance detection is the first individual neutrino proven to be of astrophysical origin. It also demonstrates IceCube’s unique contributions to multimessenger astrophysics, which uses light, particles and gravitational waves to study the cosmos. The result also opens up a new chapter of neutrino astronomy because it starts to disentangle neutrinos from antineutrinos.
“Previous measurements have not been sensitive to the difference between neutrinos and antineutrinos, so this result is the first direct measurement of an antineutrino component of the astrophysical neutrino flux,” says Lu, one of the main analyzers of this paper.
“There are a number of properties of the astrophysical neutrinos’ sources that we cannot measure, like the physical size of the accelerator and the magnetic field strength in the acceleration region,” says Yuan, an assistant scientist at the Wisconsin IceCube Particle Astrophysics Center and another main analyzer. “If we can determine the neutrino-to-antineutrino ratio, we can directly investigate these properties.”
The result also demonstrates the value of international collaboration. IceCube is operated by over 400 scientists, engineers, and staff from 53 institutions in 12 countries, together known as the IceCube Collaboration. The main analyzers on this paper worked together across Asia, North America, and Europe.

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To confirm the detection and make a decisive measurement of the neutrino-to-antineutrino ratio, the IceCube Collaboration wants to see more Glashow resonances. A proposed expansion of the IceCube detector, IceCube-Gen2, would enable the scientists to make such measurements in a statistically significant way. The collaboration recently announced an upgrade of the detector that will be implemented over the next few years, the first step toward IceCube-Gen2.
Glashow, now an emeritus professor of physics at Boston University, echoes the need for more detections of his eponymous resonance events.
“To be absolutely sure, we should see another such event at the very same energy as the one that was seen,” he says. “So far there’s one, and someday there will be more.”
This work was supported in part by the National Science Foundation (grants OPP-1600823 and PHY-191360.

In the first study of the genomic architecture of the human placenta, scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators have confirmed that the normal structure of the placenta is different to any other human organ and resembles that of a tumour, harbouring many of the same genetic mutations found in childhood cancers.
The study, published today (10 March 2021) in Nature, found evidence to support the theory of the placenta as a ‘dumping ground’ for genetic defects, whereas the fetus corrects or avoids these errors. The findings provide a clear rationale for studying the association between genetic aberrations and birth outcomes, in order to better understand problems such as premature birth and stillbirth.
In the earliest days of pregnancy, the fertilized egg implants into the wall of the uterus and begins dividing from one cell into many. Cells differentiate into various types of cell and some of them will form the placenta. Around week ten of pregnancy, the placenta begins to access the mother’s circulation, obtaining oxygen and nutrients for the fetus, removing waste products and regulating crucial hormones.
It has long been known that the placenta is different from other human organs. In one to two per cent of pregnancies, some placental cells have a different number of chromosomes to cells in the fetus — a genetic flaw that could be fatal to the fetus, but with which the placenta often functions reasonably normally.
Despite this genetic robustness, problems with the placenta are a major cause of harm to the mother and unborn child, such as growth restriction or even stillbirths.
This new study is the first high-resolution survey of the genomic architecture of the human placenta. Scientists at the Wellcome Sanger Institute and the University of Cambridge conducted whole genome sequencing of 86 biopsies and 106 microdissections from 42 placentas, with samples taken from different areas of each organ.

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The team discovered that each one of these biopsies was a genetically distinct ‘clonal expansion’ — a cell population descended from a single common ancestor — indicating a clear parallel between the formation of the human placenta and the development of a cancer.
Analysis also identified specific patterns of mutation that are commonly found in childhood cancers, such as neuroblastoma and rhabdomyosarcoma, with an even higher number of these mutations in the placenta than in the cancers themselves.
Professor Steve Charnock-Jones, a senior author of the study from the University of Cambridge, said: “Our study confirms for the first time that the placenta is organised differently to every other human organ, and in fact resembles a patchwork of tumours. The rates and patterns of genetic mutations were also incredibly high compared to other healthy human tissues.”
The team used phylogenetic analysis to retrace the evolution of cell lineages from the first cell divisions of the fertilised egg and found evidence to support the theory that the placenta tolerates major genetic flaws.
In one biopsy, the researchers observed three copies of chromosome 10 in each cell, two from the mother and one from the father, instead of the usual one copy from each parent. But other biopsies from the same placenta and from the fetus carried two copies of chromosome 10, both from the mother. A chromosomal copy number error such as this in any other tissue would be a major genetic flaw.
Professor Gordon Smith, a senior author of the study from the University of Cambridge, said: “It was fascinating to observe how such a serious genetic flaw as a chromosomal copy number error was ironed out by the baby but not by the placenta. This error would have been present in the fertilized egg. Yet derivative cell populations, and most importantly those that went on to form the child, had the correct number of copies of chromosome 10, whereas parts of the placenta failed to make this correction. The placenta also provided a clue that the baby had inherited both copies of the chromosome from one parent, which can itself be associated with problems.”
Now that the link between genetic aberrations in the placenta and birth outcomes has been established, further studies using larger sample sizes could help to uncover the causes of complications and diseases that arise during pregnancy.
Dr Sam Behjati, a senior author of the study from the Wellcome Sanger Institute, said: “The placenta is akin to the ‘wild west’ of the human genome, completely different in its structure from any other healthy human tissue. It helps to protect us from flaws in our genetic code, but equally there remains a high burden of disease associated with the placenta. Our findings provide a rationale for studying the association between genetic aberrations in the placenta and birth outcomes at the high resolution we deployed and at massive scale.”

When the body detects a pathogen, such as bacteria or viruses, it mounts an immune system response to fight this invader. In some people, the immune system overreacts, resulting in an overactive immune response that causes the body to injure itself, which may prove fatal in some cases.
Now, scientists from Nanyang Technological University, Singapore (NTU Singapore) have created a compound that could help to reduce this overactivation without impairing the body’s entire immune response.
An overactive immune system leads to many autoimmune disorders — when the immune system mistakenly attacks healthy tissues — such as rheumatoid arthritis and type 1 diabetes. More recently, it has also been linked to severe COVID-19 infections, in which immune-system signalling proteins ramp up to dangerous levels, leading to damage to the body’s own cells.
This compound designed by the NTU research team, called ASO-1, targets tyrosine kinase 2 (TYK2), a member from the Janus kinase (JAK) family of enzymes that play a key role in regulating the body’s immune response. A recent study led by the University of Edinburgh and published in the leading scientific journal Nature found that high levels of TYK2 have been associated with severe COVID-19 .
Through lab experiments using human cells grown in a dish, the NTU scientists found that ASO-1 potently reduced TYK2 levels over a sustained period and inhibited immune signalling pathways that have been associated with autoimmune disorders.
This points to the potential of the ASO-1 compound forming the basis for treatment of autoimmune conditions, said the team led by Professor Phan Anh Tuan from NTU Singapore’s School of Physical and Mathematical Sciences (SPMS).

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Professor Phan, who is also the interim director of the NTU Institute of Structural Biology, said: “Human genetic studies have suggested that deactivating TYK2 could provide protection against a broad range of autoimmune conditions such as rheumatoid arthritis, psoriasis, lupus, and type 1 diabetes.”
Dr Lim Kah Wai, NTU senior research fellow and co-lead author of the study, added: “With the UK-led study of critically ill COVID-19 patients published in Nature linking high TYK2 expression to severe COVID-19, ASO-1 could be a therapeutic agent worth investigating further. We are planning to conduct further pre-clinical work to validate its therapeutic potential.”
The findings were published in February in the scientific journal ImmunoHorizons, a publication of The American Association of Immunologists, and the research team has filed a patent for the compound they designed.
Targeting genetic material that leads to TYK2 production
A number of drugs that reduce inflammation resulting from an overactive immune response target the Janus kinase (JAK) family of four proteins: JAK1, JAK2, JAK3 and TYK2.

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Recently, TYK2 has emerged as researchers’ preferred target. As the structures of the four members are highly similar, it is important to selectively target TYK2 to limit unwanted side effects.
The ASO-1 compound designed by the NTU research team is an antisense oligonucleotide (ASO). ASOs are a type of RNA therapeutics — they target the messenger RNA (mRNA), which carries genetic instructions that cells ‘read’ to make proteins. ASO-1 is designed to bind to TYK2 mRNA, thus preventing cells from producing TYK2 protein.
The research team conducted lab experiments on human cell cultures and found ASO-1 to be highly potent and selective for TYK2, with no effect against the other JAK proteins. Dr Lim noted that this high potency of ASO-1 rivals that of recent ASO drug candidates that have advanced to clinical trials or have been approved for clinical use.
The NTU team discovered ASO-1 from over 200 potentially effective ASOs, which were designed based on their in-house expertise on nucleic acids.
The team has established an integrated platform spanning the design, synthesis, and cellular testing of RNA therapeutics. TYK2 stands among a range of therapeutic targets for immunology and cancer therapy, which is the primary focus of the team.
The NTU researchers plan to partner several academic collaborators to test ASO-1 in animal models and are open to industrial collaboration on the development of the ASO-1 compound towards clinical use.