Category Archives: Human Genetics

The flight simulator hidden in Office 97's Excel is a famous example, as is the Book of Mozilla hidden in the current Firefox browser (type about:mozilla in the address line).

The development of human beings from fertilised eggs to an adult body is often described as a genetic program. Is it possible that, like a computer program, our genetic system contains easter eggs accessible only from precise and unusual conditions?

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A US-based team, consisting of Sam Kriegman, Douglas Blackiston, Michael Levin and Josh Bongard, has recently published a paper suggesting the answer is yes.

The team are pioneering the use of tiny autonomous robots made from living cells, with the hope they may be useful in fields such as medicine: imagine robots that can patrol the body and repair it.

Their latest work sought a way for their biorobots to reproduce, and began with a particular cell type from early frog embryos. Like all frog cells, these contained the normal genetic program that controls the familiar life cycle, from egg to tadpole to frog to more eggs.

The researchers did nothing to alter this natural genome. Instead, they placed the cells in culture, and piled some of them into small mounds while leaving the others as scattered single cells.

The mounds matured and gained the ability to move, thanks to the development and beating of small whip-like protrusions, cilia, on their lower surface. As they moved, the mounds began to 'bulldoze' the scattered cells in their path into new mounds.

The new mounds slowly matured and gained the ability to move too. Careful optimization of the starting mound made this process more efficient, with a C shape turning out to be ideal.

With the best designs, the new mounds which were bulldozed into existence by the first generation, could then bulldoze further cells to make new mounds, and so on.

The researchers achieved their goal of a reproducing, living robot and, along the way, revealed something unexpected about the genetic program of the frog.

Until now, we knew only one option for frog embryo cells: make a frog, which will mate and make more embryos. This new work shows that, given peculiar starting conditions, embryo cells can 'reproduce' not by way of mating but by moving scattered single cells to create a new entity. It is a simple but wholly unexpected lifecycle: a bizarre easter egg hiding in the normal developmental program.

For now, this discovery has left scientists scratching their heads, but raises questions about the presence of easter eggs within in a developmental program. Are they accidents, unavoidable accompaniments to the main program, or do they have a function?

And, importantly, can we use them for useful biotechnological or medical purposes?

Jamie A Davies is professor of experimental anatomy, the dean of education at the University of Edinburgh, and a fellow of the Royal Society of Edinburgh. This article expresses his own views. The RSE is Scotland's national academy, bringing great minds together to contribute to the social, cultural and economic well-being of Scotland. Find out more at rse.org.uk and @RoyalSocEd

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Human genetics: 'Easter eggs' in the code of life could revolutionise healthcare with living robots that patrol the body and repair it Professor...

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Joint analysis of functionally related genes yields further candidates associated with Tetralogy of Fallot | Journal of Human Genetics - Nature.com

Genes are like Egyptian hieroglyphs. Thanks to advances in whole-genome sequencing, its increasingly easy to read each DNA letter. But the strings of A, T, C, and G bring up a second puzzle: what, if anything, do they mean?

Its a problem that has haunted biologists since the completion of the Human Genome Project. By tapping into our genetic base code, the project assumed, wed be able to master control of inherited diseases, edit them at will, and easily predict the consequences of any gene that laid the foundation for our bodies, functions, and lives.

The vision didnt exactly work out. DNA sequences, while capturing extremely powerful genetic information, dont necessarily translate to indicating how our bodies behave. Genes can turn on or off in different tissues depending on the cells need. Reading a DNA sequence for any gene is like parsing the base code of a cells internal program. Theres the raw genetic codethe genotypewhich determines the phenotype, lifes software that controls how cells behave. Linking the two has taken decades of painstaking experiments, slowly building up an encyclopedia of knowledge that decodes the influence of a gene on biological functions.

A new study ramped up the effort. Led by Drs. Thomas Norman and Jonathan Weissman at Memorial Sloan Kettering Cancer Center in New York and the University of California, San Francisco, respectively, the team built a Rosetta Stone for translating genotypes to phenotypes, with the help of CRISPR.

They went big. Changing gene expression in over 2.5 million human cells, the tech, dubbed Perturb-seq, comprehensively mapped how each genetic perturbation alters the cell. The technology centers around a sort of CRISPR on steroids. Once introduced into cells, Perturb-seq rapidly changes thousands of genesa brutal shakeup at the genomic scale to see how single cells respond.

In other words, Perturb-seq is a large-scale tool that can help scientists translate DNA code to functiona Rosetta Stone for uncovering our cells inner workings. Years in the making, the dataset is open for anyone to explore.

I think this dataset is going to enable all sorts of analyses that we havent even thought up yet by people who come from other parts of biology, and suddenly they just have this available to draw on, saidNorman.

Whats the function of a gene? Its easy to think that genes are your destiny but thats far from the truth. Environmental factors, such as a massive bowl of spaghetti or a walk along the beach, can easily change gene expression, bodily functions, and potentially your body and mind.

If thats the case, whats the point of sequencing whole genomes if the outcome is always in flux? A central goal of genetics is to define the relationships between genotype and phenotype, the authors said. In other words, what does any gene actually do?

Scientists have long sought to build a bridge between genotype and phenotype. Its a painstaking process. One method, for example, perturbs genes that may be related to a disorder one by one and observes the cells behavior. Dubbed forward genetics, the idea is gene-focused rather than focusing on the phenotype. An alternative approach, reverse genetics, dives deep into how a body or mind changes with a specific genetic edit.

Each method is an uphill struggle. With over 20,000 genes in our bodies and every cell behaving slightly differently (even with the same genetic changes), deciphering a genes function often takes years, if not decades.

Is there any way to speed the process up?

Enter CRISPR. Long revered as a genetic editing multitool, the method has further blossomed into a biological translator. At its heart is a technology dubbed Perturb-seq, first published in 2016 to dissect the expression of genes. Perturb-seq makes it possible to follow the consequences of turning a gene on or off in a single cell. The method rapidly rose to fame in 2020 for its efficiency at altering multiple genes at once.

Its a huge win for cell biology, said the team. While scientists have readily chipped away at the massive web connecting genes and proteins, nailing down the role of individual genes has been a struggle. We often take all the cells where gene X is knocked down and average them together to look at how they changed, said Weissman. But sometimes when you knock down a gene, different cells that are losing that same gene behave differently, and that behavior may be missed by the average.

The idea behind Perturb-seq is pretty simple. Imagine a toddler breaking stuff and realizing what hes done after seeing the consequences. Perturb-seq uses CRISPR-Cas9 to silence multiple genes at once, which may sometimes change a cells behavior. While powerful, the tool has been hard to scale, studying at most a few hundred genetic perturbations at once for pre-defined biological questions.

So why not expand the method to the whole genome?

The advantage of Perturb-seq is it lets you get a big dataset in an unbiased way, said Norman. No one knows entirely what the limits are of what you can get out of that kind of dataset. Now, the question is, what do you actually do with it?

In the new study, the team first found the magic sauce for making genome-wide changes in human cells with CRISPR. A major point was to optimize a library of guide RNAs (sgRNAs), the bloodhounds that track down a gene. Next, they captured cells infected with CRISPR and analyzed their gene expression. Overall, the team focused on nearly 2,000 genes. Cross-referencing changed genes with each cells phenotype, they then clustered genes into networks that linked to a cellular outcome.

One enigmatic gene stood out: C7orf26. Nixing it with CRISPR changed how a cell builds a huge molecular complex, dubbed the Integrator, which helps make molecules that control gene activity. Before Perturb-seq, C7orf26 had never been associated with the complex before.

In another analysis, the team found a subset of genes that changes how daughter cells inherit the parent genome. For example, removing some genes altered the distribution of chromosomes as a cell divides. Adding or removing a chromosome can fundamentally change our biology, such as by leading to Down Syndrome.

To Norman, this aspect is the most interesting part of Perturb-seq. It captures a phenotype that you can only get using a single-cell readout. You cant go after it any other way.

This database is just the start. The team is looking to use Perturb-seq on other human cell types, and all the data is available for collaboration. With the rise of Ultima Genomics, an ultra-low-cost genomic sequencing solution, single-cell CRISPR screens are likely to play an even bigger role in biotechnology, such as in analyzing the genomes of iPSCs (induced pluripotent stem cells).

To Weissman, it may even spark a shift in how we approach cellular mysteries. Rather than defining ahead of time what biology youre going to be looking at, you have this map of the genotype-phenotype relationships, and you can go in and screen the database without having to do any experiments, he said.

Image Credit: Jen Cook/Chrysos Whitehead Institute

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Scientists Used CRISPR to Trace Every Human Gene to Its Function - Singularity Hub

Courtesy of Dana-Farber Cancer Institute

Researchers from the Dana-Farber Cancer Institute have found a way to look deeper into a long-neglected, non-coding portion of the human genome, uncovering mechanisms that might drive or suppress cancer development.

Since scientists at the Human Genome Project completedthe sequencing of the entire human genome, extensive data has become available to suggest that the coding region of the genome is involved in gene regulation, while the non-coding region merely exists as fluff. The Dana-Farber researchers' findings, published in Nature Genetics earlier this week, proved this notion wrong by showing that the non-coding portion of the human genome plays a role in gene epigenetics, or factors that influence DNA to be wound more tightly or loosely.

While the coding regions are directly linked to gene expression, the non-coding region can regulate gene activity by influencing the environment around it. The Dana-Farber team jump-started this new area of research by accumulating a database of mutations that have links to biological mechanisms by way of epigenetic influence.

Alexander Gusev, Ph.D., of Dana-Farber, the Eli and Edythe L. Broad Institute, Brigham and Women's Hospital and co-author of the paper, alongside Dana-Farber's Dennis Grishin, Ph.D., commented on the findings.

"Studies have identified an enormous number of mutations across the genome that are potentially involved in cancer," Gusev said. "The challenge has been understanding the biology by which these variations increase cancer risk. Our study has uncovered an important part of that biology...more than 300 mutations have been identified that are associated with an increased risk of the disease."

He added, "Less than 10% of them are actually within genes. The rest are in 'desert' regions, and it hasn't been clear how they influence disease risk."

Typically, geneticists make use of a technology called genome-wide association studies (GWAS) to cross-reference the mutations in the coding genome of healthy people against those in cancer patients. The data collected from this technique highlights a level of scientific neglect that would leave many scratching their heads - less than 30 of the 300 identified cancer-linked mutations occur in the genes or coding region. The remaining majority represent the non-coding region.

Despite this information, the scientific community has yet to dig deeper into the implications. That is, before the investigators at Dana-Farber got involved.

The research team used GWAS data for a specific cancer type and compared it against epigenetic changes. This was done in hopes of finding a link between epigenetic environment regulation and the presence of a non-coding mutation. This process is referred to as an overlay study.

Gusev explained, "If a mutation has an effect on disease, that effect will probably be too subtle to capture at the level of gene expression but may not be too subtle to capture at the level of local epigenetics - what is happening right around the mutation."

The publishing of the study is timely. With the American Society of Clinical Oncology (ASCO) Annual Meeting that was held in Chicago from June 3 to 7, and the 27th Congress of the European Hematology Association (EHA) 2022, held in Vienna, Austria, and virtually, from June 9 to 12, all eyes have been on cancer research and data.

This area of study may open new doors for researchers that wish to get to the very root of why a gene is off or on, leading to the development of cancer.

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Researchers Link Mutations in Long Neglected Non-Coding Genome to Cancer - BioSpace

Its a quirk of history that the foundations of modern biology and as a consequence, some of the worst atrocities of the 20th century should rely so heavily on peas. Cast your mind back to school biology, and Gregor Mendel, whose 200th birthday we mark next month. Though Mendel is invariably described as a friar, his formidable legacy is not in Augustinian theology, but in the mainstream science of genetics.

In the middle of the 19th century, Mendel (whose real name was Johann Gregor was his Augustinian appellation) bred more than 28,000 pea plants, crossing tall with short, wrinkly seeds with smooth, and purple flowers with white. What he found in that forest of pea plants was that these traits segregated in the offspring, and did not blend, but re-emerged in predictable ratios. What Mendel had discovered were the rules of inheritance. Characteristics were inherited in discrete units what we now call genes and the way these units flowed through pedigrees followed neat mathematical patterns.

These rules are taught in every secondary school as a core part of how we understand fundamental biology genes, DNA and evolution. We also teach this history, for it is a good story. Mendels work, published in 1866, was being done at the same time as Darwin was carving out his greatest idea. But this genius Moravian friar was ignored until both men were dead, only to be rediscovered at the beginning of the new century, which resolved Darwinian evolution with Mendelian genetics, midwifing the modern era of biology.

But theres a lesser-known story that shaped the course of the 20th century in a different way. The origins of genetics are inextricably wedded to eugenics. Since Plato suggested the pairing of high-quality parents, and Plutarch described Spartan infanticide, the principles of population control have been in place, probably in all cultures. But in the time of Victorian industrialisation, with an ever-expanding working class, and in the wake of Darwinian evolution, Darwins half-cousin, Francis Galton, added a scientific and statistical sheen to the deliberate sculpting of society, and he named it eugenics. It was a political ideology that co-opted the very new and immature science of evolution, and came to be one of the defining and most deadly ideas of the 20th century.

The UK came within a whisker of having involuntary sterilisation of undesirables as legislation, something that Churchill robustly campaigned for in his years in the Asquith government, but which the MP Josiah Wedgwood successfully resisted. In the US though, eugenics policies were enacted from 1907 and over most of the next century in 31 states, an estimated 80,000 people were sterilised by the state in the name of purification.

American eugenics was faithfully married to Mendels laws though Mendel himself had nothing to do with these policies. Led by Charles Davenport a biologist and Galton devotee the Eugenics Record Office in Cold Spring Harbor, New York, set out in 1910 to promote a racist, ableist ideology, and to harvest the pedigrees of Americans. With this data, Davenport figured, they could establish the inheritance of traits both desirable and defective, and thus purify the American people. Thus they could fight the imagined threat of great replacement theory facing white America: undesirable people, with their unruly fecundity, will spread inferior genes, and the ruling classes will be erased.

Pedigrees were a major part of the US eugenics movement, and Davenport had feverishly latched on to Mendelian inheritance to explain all manner of human foibles: alcoholism, criminality, feeblemindedness (and, weirdly, a tendency to seafaring). Heredity, he wrote in 1910, stands as the one great hope of the human race; its saviour from imbecility, poverty, disease, immorality, and like all of the enthusiastic eugenicists, he attributed the inheritance of these complex traits to genes nature over nurture. It is from Davenport that we have the first genetic studies of Huntingtons disease, which strictly obeys a Mendelian inheritance, and of eye colour, which, despite what we still teach in schools, does not.

One particular tale from this era stands out. The psychologist Henry Goddard had been studying a girl with the pseudonym Deborah Kallikak in his New Jersey clinic since she was eight. He described her as a high-grade feeble-minded person, the moron, the delinquent, the kind of girl or woman that fills our reformatories. In order to trace the origin of her troubles, Goddard produced a detailed pedigree of the Kallikaks. He identified as the founder of this bloodline Martin Kallikak, who stopped off en route home from the war of independence to his genteel Quaker wife to impregnate a feeble-minded but attractive barmaid, with whom he had no further contact.

In Goddards influential 1912 book, The Kallikak Family: A Study in the Heredity of Feeble-Mindedness, he traced a perfect pattern of Mendelian inheritance for traits good and bad. The legitimate family was eminently successful, whereas his bastard progeny produced a clan of criminals and disabled defectives, eventually concluding with Deborah. With this, Goddard concluded that the feeble-mindedness of the Kallikaks was encoded in a gene, a single unit of defective inheritance passed down from generation to generation, just like in Mendels peas.

A contemporary geneticist will frown at this, for multiple reasons. The first is the terminology feeble-minded, which was a vague, pseudopsychiatric bucket diagnosis that we presume included a wide range of todays clinical conditions. We might also reject his Mendelian conclusion on the grounds that complex psychiatric disorders rarely have a single genetic root, and are always profoundly influenced by the environment. The presence of a particular gene will not determine the outcome of a trait, though it may well contribute to the probability of it.

This is a modern understanding of the extreme complexity of the human genome, probably the richest dataset in the known universe. But a meticulous contemporary analysis is not even required in the case of the Kallikaks, because the barmaid never existed.

Martin Kallikaks legitimate family was indeed packed with celebrated achievers men of medicine, the law and the clergy. But Goddard had invented the illegitimate branch, by misidentifying an unrelated man called John Wolverton as Kallikaks bastard son, and dreaming up his barmaid mother. There were people with disabilities among Wolvertons descendants, but the photos in Goddards book show some of the children with facial characteristics that are associated with foetal alcohol syndrome, a condition that is entirely determined not by genetic inheritance, but by exposure to high levels of alcohol in utero. Despite the family tree being completely false, this case study remained in psychology textbooks until the 1950s as a model of human inheritance, and a justification for enforced sterilisation. The Kallikaks had become the founding myth of American eugenics.

The German eugenics movement had also begun at the beginning of the 20th century, and grown steadily through the years of the Weimar Republic. By the time of the rise of the Third Reich, principles such as Lebensunwertes Leben life unworthy of life were a core part of the national eugenics ideology for purifying the Nordic stock of German people. One of the first pieces of legislation to be passed after Hitler seized power in 1933 was the Law for the Prevention of Genetically Diseased Offspring, which required sterilisation of people with schizophrenia, deafness, blindness, epilepsy, Huntingtons disease, and other conditions that were deemed clearly genetic. As with the Americans tenacious but fallacious grip on heredity, most of these conditions are not straightforwardly Mendelian, and in one case where it is Huntingtons the disease takes effect after reproductive age. Sterilisation had no effect on its inheritance.

The development of the Nazis eugenics programmes was supported intellectually and financially by the American eugenicists, erroneously obsessed as they were with finding single Mendelian genes for complex traits, and plotting them on pedigrees. In 1935, a short propaganda film called Das Erbe (The Inheritance) was released in Germany. In it, a young scientist observes a couple of stag beetles rutting. Confused, she consults her professor, who sits her down to explain the Darwinian struggles for life and shows her a film of a cat hunting a bird, cocks sparring. Suddenly she gets it, and exclaims, to roars of laughter: Animals pursue their own racial policies!

The muddled propaganda is clear: nature purges the weak, and so must we.

The film then shows a pedigree of a hunting dog, just the type that you might get from the Kennel Club today. And then, up comes an animation of the family tree of the Kallikaks, on one side Erbgesunde Frau and on the other, Erbkranke Frau genetically healthy and hereditarily defective women. On the diseased side, the positions of all of the miscreants and deviants pulse to show the flow of undesirable people through the generations, as the voiceover explains. Das Erbe was a film to promote public acceptance of the Nazi eugenics laws, and what follows the entirely fictional Kallikak family tree is its asserted legacy: shock images of seriously disabled people in sanatoriums, followed by healthy marching Nazis, and a message from Hitler: He who is physically and mentally not healthy and worthy, may not perpetuate his suffering in the body of his child. Approximately 400,000 people were sterilised under this policy. A scientific lie had become a pillar of genocide in just 20 years.

Science has and will always be politicised. People turn to the authority of science to justify their ideologies. Today, we see the same pattern, but with new genetics. After the supermarket shootings in Buffalo in May, there was heated discussion in genetics communities, as the murderer had cited specific academic work in his deranged manifesto, legitimate papers on the genetics of intelligence and the genetic basis of Jewish ancestry, coupled with the persistent pseudoscience of the great replacement.

Science strives to be apolitical, to rise above the grubby worlds of politics and the psychological biases that we are encumbered with. But all new scientific discoveries exist within the culture into which they are born, and are always susceptible to abuse. This does not mean we should shrug and accept that our scientific endeavours are imperfect and can be bastardised with nefarious purpose, nor does it mean we should censor academic research.

But we should know our own history. We teach a version of genetics that is easily simplified to the point of being wrong. The laws in biology have a somewhat tricksy tendency to be beset by qualifications, complexities and caveats. Biology is inherently messy, and evolution preserves what works, not what is simple. In the simplicity of Mendels peas is a science which is easily co-opted, and marshalled into a racist, fascist ideology, as it was in the US, in Nazi Germany and in dozens of other countries. To know our history is to inoculate ourselves against it being repeated.

This article was amended on 20 June 2022. The mass shooting in Buffalo, US, in May 2022 was at a supermarket, not a school as an earlier version said.

Control: The Dark History and Troubling Present of Eugenics by Adam Rutherford is published by Weidenfeld & Nicolson (12.99). To support the Guardian and Observer order your copy at guardianbookshop.com. Delivery charges may apply

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Where science meets fiction: the dark history of eugenics - The Guardian

Beverly, Massachusetts(Newsfile Corp. June 20, 2022) NonExomics has announced the launch of new technology to explore the dark genome for rapid diagnosis and treatment of many common diseases like cancer, bipolar disorder, cardiovascular diseases, and schizophrenia. The Human Genome Project was a massive international 13-year research project that ran from 1990 to 2003 and identified the complete DNA sequence of a human being. It helped to identify over 1,400 disease genes. Nevertheless, the Human Genome Project failed to give a complete picture of human DNA. As much as 98% of human DNA does not code for proteins and does not fit in with the conventional parameters for DNA. This is now known as the dark genome. Hidden in this dark genome, there are many novel proteins that could play a major role in the activity of thousands of genes and thus influence diseases like autism, heart disease, and cancer. Current therapies target only 2% of the human genome.

NonExomics specializes in new technology that effectively leverages AI and proteogenomics (which studies how the DNA in a cell is linked to the proteins made by that cell) to identify hundreds of new disease-linked biomarkers that have been linked to over 1,365 diseases in human beings.

Currently, NonExomics is engaged in research that identifies whether these novel proteins can function as drug targets for therapeutic purposes or can be used for diagnostic processes. NonExomics has ambitious plans to partner or license its discoveries to other companies and labs to develop new therapies and diagnostics.

NonExomics is the first mover in this space and has developed this technology that effectively combines artificial intelligence, proteomics, transcriptomics, and genomics for quicker diagnosis and treatment of diseases that are currently considered to be incurable or difficult to manage.

Dr. Prabakaran left his position with the Department of Genetics at the University of Cambridge to set up NonExomics and has raised seed capital to fund the commercialization of his teams discoveries. The company was one of the seven genomics startups that was chosen by Illumina for investment as part of its accelerator program. In addition to its Boston site, NonExomics has sites in Cambridge, UK, and Chennai, India. As the first firm to explore the world of the dark genome, NonExomics is on track to make a real impact in the world of healthcare.

So far, NonExomics has validated the transcript and protein expression of almost 248,135 non-exomic regions. Mutations in these regions have been linked to diseases like cancer, schizophrenia, and rare diseases like age-related macular degeneration and amyotrophic lateral sclerosis (ALS). As of now, NonExomics has made significant headway in research linked to the diagnosis and treatment of 22 cancers, bipolar disorder, schizophrenia, and 750 rare diseases over an eight-year period.

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Name: Dr. Sudhakaran PrabakaranEmail: [emailprotected]

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NonExomics Unveils Technology to Decode Dark Genome for Diagnosis and Treatment of Diseases Like Cancer - Digital Journal

Kri Stefnsson has the blood of almost all of his countrymen stored beneath his office. He is a visionary Icelandic doctor, and a quarter century ago, he had an ambitious idea: to use his native country, a volcanic island near the Arctic circle, as a giant laboratory to examine the essence of human beings. Since then, more than half the population, some 180,000 volunteers, have responded to Stefnssons call. His company, deCODE, has analyzed all of their DNA, revealing thousands of genetic variants linked to common illnesses including cancer and Alzheimers. Francis Collins, ex-director of the United States National Institutes of Health, calls Stefnssons findings the language of God.

Reykjaviks strange sunlight filters through the window, and Stefnsson reflects, pensive, on the religious metaphor. After 20 long seconds of silence, the doctor begins to speak. I have difficulties with the kind of God Francis Collins believes in. If I were to run into the God Francis Collins believes in on the street today, the omnipotent God who can do everything, I would probably tell him that he was an unbelievable asshole. Why do you let war happen? Why do you let young children die?, he inquires, gazing into space, as if he were speaking to a god present in the room.

A few meters below Stefnssons feet there is an immense freezer chamber, at 24 degrees Celsius below zero, in which robot hands handle tubs with blood samples from those 180,000 generous Icelanders who have offered their blood and medical history to a for-profit private company. Since 1996, deCODE has discovered thousands of risk factors for illness, as well as some genetic keys to the human personality, which have been published in the worlds best scientific journals.

Everything is nearby in Reykjavik. A few minutes walk from Stefnssons office is Icelands National Museum. An ancient manuscript recounts that Norwegian vikings settled in the island in the year 874. Near the museums entrance, below a glass panel in the floor, lies the skeleton of one of the islands first inhabitants: a warrior buried with his imposing sword and his horse. The halls are lined with Viking drinking horns, images of fantastic creatures and references to forgotten deities, like Thor and Odin, who once terrorized humanity and now only demonstrate, as Stefnsson says, that gods are human inventions.

The Spanish geneticist Carles Lalueza, a long-time collaborator of deCODE and director of Barcelonas Natural Science Museum, notes, half-joking, that as incredible as it seems, all Icelanders are related. Hes not exaggerating. Some 10,000 peoplelargely Viking men from contemporary Norway and women abducted from the British islessettled on the island over just six decades after 874. Almost all current-day Icelanders can trace their family tree to one of those pioneers. Stefnsson, for example, says he is a descendant of Egill Skallagrimsson, a man born in 910 who was one of the great Icelandic poets and, as the doctor tends to joke, one of the islands ugliest inhabitants. The lack of genetic diversity has made Iceland an ideal place to look for the DNA errors that produce human illnesses.

Stefnsson ruminates on his thoughts about death. One of his companys most recent advancements is a method to predict a persons death in five years. The researchers followed 23,000 Icelanders for 14 years, measuring the blood levels of thousands of proteins. The new tool was able to classify people in their sixties and seventies according to their proximity to death. In the group classified as high-risk, 88% of participants died. In the low-risk group, only 1% passed away. Stefnsson recognizes that this ability to predict someones death is chilling.

The doctor receives EL PAS after a visit to his facilities organized and paid by Amgen, the American pharmaceutical company that bought deCODE for 320 million in 2012. The Icelandic company couldnt figure out how to convert its scientific discoveries into capital. In 2009, when the entire Nordic country sank in an economic crisis that ended up with dozens of corrupt financiers in prison, the company fell into bankruptcy. Stefnsson is a peculiar and controversial entrepreneur: he speaks more about poetry than business. He argues that a good scientist should read at least 50 novels every year. The equipment you think with is your language. And to be able to think anything new you have to be good at using language. You have to be an acrobat of language, he says.

Stefnsson says that he is sad and depressed. Six months ago, his wife of 53 years died. He is still learning to live without her. The doctor, who usually spends his vacations in Spain and adores poets like Antonio Machado and Octavio Paz, writes poetry to move through his pain. He asks himself a question out loud: What is life? He responds without lyricism: Life are all self-assembling systems that contain DNA, allow DNA to replicate and on the basis of the replicated DNA form other self-assembly system of the same kind.

To Stefansson, that is all. DNA, the molecule with the instructions to form a human being from a fertilized egg, just wants to multiply itself. It is a recipe, written in carbon, hydrogen, oxygen, nitrogen and phosphorus, that commands every human cell. It is clear that DNA does not exist to serve the life forms. The life forms exist to serve DNA. They exist to allow DNA to persist on Earth. Preservation of DNA is the purpose of life, he explains with a bitter smile. Thats not very romantic, but there is no God. Which is unfortunate, because it would be really convenient to have one, he adds ironically.

Stefansson remembers a poem he wrote one day in 1996, when the birth of Dolly the sheep, the first mammal cloned from another animals adult cell, led him to reframe the meaning of life. Where do I find, lost in the brightness of a sunlit day, the happiness of an unhappy man, fortunate only to be just one copy of himself. Everything else stinks, he recites, gesticulating.

Stefanssons scientific production is unmatched. He has authored 5% of the studies published in the journal Nature Genetics in the last decade. But humanity is more complex than he had imagined when he founded deCODE. In 2003, Stefansson proclaimed that he hoped to develop at least 10 pharmaceuticals through his discoveries of genetic variants associated with illnesses. They still dont exist. There are things in development now who I hope will make it to the market sooner or later, the doctor says.

The challenge is massive. The scientific community has known since 1980 that certain DNA mutations in a gene called KRAS, cause cancer in millions of people. But the first KRAS inhibitor medication reached hospitals only last year. Sotorasib, developed by Amgen, inhibits a specific mutation, called KRAS G12C, that is involved in 13% of non-small-cell lung cancer cases, the most common lung tumor. Biochemist Ray Deshaies, scientific vice-president of Amgen, explained at a Reykjavik press conference that [the delay of over three decades] wasnt because we didnt know what we wanted to do, which was inhibit the mutation in KRAS, its just that we had no idea how to do it.

Stefansson stretches his arms over the table. -Its easier to get a man to the Moon than to make a really good drug. But nevertheless, the industry does it, he says. The doctor recalls the case of AIDS, caused by a virus detected in 1983, which has killed over 36 million people but now can be controlled with a single daily pill. Which is beautiful. You have to admit that. So even though the pharmaceutical industry is a little bit annoying, it at least stands out, he observes.

Amgen is one of the 15 largest pharmaceutical companies in the world, with earnings of 7 billion last year. Its price policy has become controversial in recent years: the drug blinatumomab, which fights an aggressive form of leukemia, appeared on the US market in 2014 for 145,000 per patient, becoming one of the most expensive cancer medications in the world.

Biologist Robert Bradway, Amgens executive director, affirmed in a Reyjavik press conference that not even one out of every 10 experimental drugs, which seem promising in animals, work in human trials. Mice are wonderful. The problem with mice is that they are mice. They always have been and always will be mice. And mice are not terribly good at predicting what will happen in humans, so what might work as a cure for obesity in mice may not work as a cure for obesity in humans, Bradway lamented. The majority of genetic variants discovered by deCODE only barely increase the risk of suffering from an illness: there are 3,000 associated with obesity, for example. But some of those mutations can reveal the mechanisms behind a pathology. Thats why Amgen decided to buy the Icelandic company in 2012.

Bradway repeats a statistic common in the pharmaceutical industry: developing a drug takes 15 years and 2.3 billion. Those data points are debated by some organizations, such as the Swiss Drugs for Neglected Diseases Initiative, which has invested only 55 million to develop an effective drug against sleeping sickness. In 2021, Amgens executive director earned over 20 million, 166 times as much as the companys average employee, according to public data from the organization.

Kari Stefansson admits the industry has its shadows. There is certainly a certain conflict between the private or the for-profit companies that are making drugs and the public interest. I can, however, tell you that theres much more of common interest than you may think, he says. The doctor remembers that, weeks before Covid-19 forced humanity to shelter in their homes, he called the directors of Amgen to ask them for permission to research the novel coronavirus. For heavens sake, do it, they answered. His data demonstrated early on that half of the people infected were asymptomatic and that children rarely got sick. Iceland resisted the terrifying first wave of Covid much better than other countries.

The Icelandic doctor does, however, have enemies in high places. Bioethics expert Henry Greely, director of Stanford Universitys Center for Law and Biosciences, has publicly spoken against Stefanssons notably abrasive personality, accusing him of taking advantage of Icelanders without sharing the earnings. On the other hand, Icelandic economist Svala Gudmundsdottir has praised the deCODE founders well-known generosity after he donated expensive medical equipment to Rekjaviks university hospital and for carrying out massive Covid tests free of charge.

The Icelandic company has the DNA of entire families on the island. The data analysis has revealed surprising keys to human personality. Stefansson speaks of genetic nurture: a parents genes, including those that their children do not inherit, mark a persons destiny. The genes that you dont have affect your grades in school, the age when you have your first child, your cholesterol levels and the number of cigarettes you smoke. I think that our free will is extraordinarily limited. Youre genetically programmed to want certain things and youre genetically programmed not to want other things, Stefansson claims. So I think free will is an illusion.

One of the best chess players in history, the American Bobby Fischer, moved to Iceland in 2005, fleeing from his countrys authorities, who sought to punish him for violating sanctions against Yugoslavia after participating in a friendly tournament in 1992. His escape to the Nordic island wasnt a coincidence. Fischer had been an idol there since 1972, when he defeated the Soviet Boris Spassky in the midst of the Cold War. The encounter was a nuclear battle over a chess board. When he returned to Iceland over three decades later, sick and close to death, Bobby Fischer became friends with Kari Stefansson.

The 62-year-old master had lost his mind, victim of a sort of paranoid psychosis, as the Icelander recalls, obsessed with Jews, black people and women. Despite it all, the two new friends spent time together in Reykjavik, occasionally having marvelous conversations. The Icelandic documentary Me and Bobby Fischer (Fridrik Gudmundsson, 2010) shows some of those memorable talks. In one of them, from a moving car, the chess player rants about genetic research and compares it to the work of physicists who brought about the atomic bomb. The discussion, a veritable philosophy class, ends in shouts, even though Stefansson began trying to make amends.

What we are doing in my company is simply trying to discover what life is about, we are not manipulating it in any way.

Just like the scientists were trying to discover what the atom is all about and look where it has led.

That has led to deeper understanding

It has led to stockpiling hydrogen bombs!

Thats not the consequence of that.

Yeeeeeeees.

That is the consequence of evil exploitation of stupid people.

The

Listen to me! If you are gonna try to put a ban on the discovery of new knowledge, you are beginning to control the world in an unpredictable manner, because you dont know what the knowledge is until it has been discovered! So how are you going to control what we can discover?

Stefnsson remembers those discussions now. Since Bobby Fischers death in 2008, deCODE has continued to illuminate human beings genetic secrets, thanks to the 180,000 Icelandic volunteers and two million other people from around the world who have participated. Other countries, including the United Kingdom, have also begun large-scale attempts to read their citizens DNA. Knowledge in and of itself is never an evil, Stefansson insists. After a quarter-century discovering genetic differences among human beings, the Icelandic doctor is left with a lesson from his remote volcanic island: We should have to remember that we are one species, we are one kind. And what separates us is so much less than what joins us. We should not use human diversity to discriminate against each other. We should celebrate human diversity.

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The island that revealed the essence of humanity - EL PAS USA

As many as one in 500 men may carry an extra sex chromosome either an X or a Y but very few of them likely know about it, a new study suggests.

The research, published June 9 in the journal Genetics in Medicine (opens in new tab), included data from more than 207,000 men who provided information to the U.K. Biobank, a repository of genetic and health data from half a million U.K.-based participants. Typically, males carry one X- and one Y-shaped sex chromosome in each of their cells, but among the study participants, there were 213 men who carried an extra X chromosome and 143 that had an extra Y.

Very few of these men either reported being diagnosed with a chromosomal abnormality or had such an abnormality noted in their medical records: Of the XXY men, only 23% had a known diagnosis, and just 0.7% of the XYY men had a diagnosis. (The potential symptoms of having an extra Y chromosome can be very subtle, which may somewhat explain the difference in diagnosis rates, according to the Genetic and Rare Diseases Information Center (opens in new tab).)

"We were surprised at how common this is," Dr. Ken Ong, a pediatric endocrinologist in the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge and a co-senior author on the study, told The Guardian (opens in new tab). "It had been thought to be pretty rare."

Previous estimates suggested that roughly 100 to 200 men out of every 100,000 are XXY, according to the National Human Genome Research Institute (opens in new tab), and an estimated 18 to 100 out of every 100,000 were thought to be XYY, the authors noted in their report.

Related: Is the Y chromosome dying out?

In all, about 0.17% of the study participants had an extra sex chromosome, or about one in 580. However, the rate observed in the study might be slightly lower than that among the general population, the study authors noted in their report. That's because U.K. Biobank volunteers tend to be healthier than the general population and have a lower-than-average incidence of genetic conditions. Based on this, the authors estimate that about one in 500 men, or 0.2%, in the general population carry an extra sex chromosome.

Having extra sex chromosomes can raise the risk of certain health conditions, and this increased risk seemed to be reflected in the Biobank volunteers' health data, the researchers reported.

For instance, Klinefelter syndrome (KS) or having an extra X chromosome as a male has been linked to reproductive problems, including infertility and delayed puberty, according to the National Human Genome Research Institute. In the study, XXY men's rate of childlessness was four times higher than that of XY men, and they were three times more likely to have started puberty late, according to a statement (opens in new tab).

A condition called 47,XYY syndrome or having an extra Y chromosome as a male was not linked to an increased rate of reproductive problems in the affected study participants, the authors reported. That said, in the past, the syndrome has been linked to other symptoms, including learning disabilities, delays in acquiring speech and motor skills, and unusually low muscle tone, according to the Genetic and Rare Diseases Information Center. These symptoms were not specifically assessed in the Biobank study.

Related: Are you genetically more similar to your mom or your dad?

However, the research did reveal a possible link between extra sex chromosomes and other conditions. Compared with XY men, both the XXY and XYY men showed higher rates of type 2 diabetes; plaque build-up in the walls of the arteries (atherosclerosis); blood clots in the veins (venous thrombosis) and lung arteries (pulmonary embolism); and chronic obstructive pulmonary disease, which obstructs airflow to the lungs.

"It is unclear why both KS and 47,XYY should show striking similarities in conferring substantially higher risks for many diseases in common," the authors wrote in their report. The mechanisms driving this increased risk will have to be explored in future studies, they said.

The study is limited in that it only included men of European ancestry who were between the ages of 40 and 70. However, "our study is important because it starts from the genetics and tells us about the potential health impacts of having an extra sex chromosome in an older population, without being biased by only testing men with certain features as has often been done in the past," Anna Murray, an associate professor of human genetics at the University of Exeter Medical School and co-senior author of the study, said in the statement.

Originally published on Live Science.

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One in 500 men may carry an extra sex chromosome (most without knowing it) - Livescience.com

Its clear to anyone that an African elephant and a garden snail are different species, but the lines blur around closely related animals. In fact, many biologists suggest there isnt a clear-cut definition of what a species really is.

It turns out that speciation is an even more complicated and messy process than previously thought.

A recent study, published in the Proceedings of the National Academy of Sciences (PNAS), looked at the separation of polar bears and brown bears into distinct species, discovering that the process of speciation is not as clear cut as we might like to believe.

Scientists have known for some time that the delineation of polar and brown bears did not stop them from mating with each other. The results presented in the paper involve an expanded dataset including genetic sequencing of an ancient polar-bear tooth to gain insights into the split between the species.

The research has implications beyond bears. The findings have similarities to discoveries about our own species evolution, and speciation more broadly.

What is a species? Thats the question, laughs Peter Cowman, senior curator of biosystematics at Queensland Museum Network, and co-appointed senior researcher at the Centre of Excellence for Coral Reef Studies at James Cook University. A species is a concept, and its important to understand that its a human construct. We need species to understand the world that we live in and the biodiversity of our planet, but nature and evolution dont necessarily care what we think a species is. As scientists we have different concepts of what a species is.

A lot of people use biological species concept the ability of two individuals to successfully produce viable, fertile offspring but thats not always the case. The polar bear and brown bear, although its uncommon, are involved in hybridisation across the two species.

A lot of people use biological species concept the ability of two individuals to successfully produce viable, fertile offspring but thats not always the case.

Because Im a phylogeneticist, or bioinformatician, I tend to lean towards what we call the phylogenetic species concept. This is all about using family trees or molecular phylogenetic trees to understand how closely related individuals are within a population or across species. But that doesnt always give the right answer, either.

Cowman told Cosmos that the PNAS paper highlights how new analytic tools are transforming the way in which we study evolution and genetics. In turn, this provides opportunities for us to better understand the basics of what a species is and where organisms fit in the ecosystem.

We really are getting into the science-fiction end of things, says Cowman. Weve got a desktop sequencer that can sequence a genome in 48 hours or less. Its the same size as an iPhone. The data were producing now is what future technology will be based on. All you have to do is look at the response to the COVID pandemic we can get genetic data and analyse it very quickly. Overnight, you get new trees for different COVID strains and understanding how new strains are popping up.

Its the same in biodiversity analysis. All these things add to how we can analyse this data really quickly and understand how different species are interacting, and especially how theyre going to change under the climate-change scenario.

Museums are a goldmine for these types of analysis, especially with this changing technology. Like analysing DNA from fossils, were able to analyse DNA from samples that are collected 80 to 100 years ago. Were able to get DNA that can solve different puzzles.

Were able to analyse DNA from samples that are collected 80 to 100 years ago. Were able to get DNA that can solve different puzzles.

An example of the power of new analysis techniques, particularly involving ancient DNA, is shown in our developing understanding of our own evolution.

Scientists once thought a common ancestor simply split into modern humans and Neanderthals. But researchers have found Neanderthal DNA in modern Eurasian people. This implies that modern human populations received an influx of genes from Neanderthals at some point in their shared evolutionary history.

The researchers of the PNAS paper, which included, scientists from the US, Finland, Norway, Denmark, Singapore and Mexico, explain that it was only later that scientists realised that this genetic intermingling also supplemented Neanderthal populations with modern human genes. In other words, interbreeding is complex and not necessarily one way.

The formation and maintenance of species can be a messy process, says study co-author Charlotte Lindqvist, associate professor of biological sciences at the University at Buffalo and a bear genetics expert.

We find evidence for interbreeding between polar bears and brown bears that predates an ancient polar bear we studied,

Whats happened with polar bears and brown bears is a neat analogue to what were learning about human evolution: that the splitting of species can be incomplete, she says. As more and more ancient genomes have been recovered from ancient human populations, including Neanderthals and Denisovans, were seeing that there was multidirectional genetic mixing going on as different groups of archaic humans mated with ancestors of modern humans. Polar bears and brown bears are another system where you see this happening.

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We find evidence for interbreeding between polar bears and brown bears that predates an ancient polar bear we studied, Lindqvist adds. And, moreover, our results demonstrate a complicated, intertwined evolutionary history among brown and polar bears, with the main direction of gene flow going into polar bears from brown bears. This inverts a hypothesis suggested by other researchers that gene flow has been unidirectional and going into brown bears around the peak of the last ice age.

Sixty-four modern polar and brown bear genomes were studied by the researchers.

Its exciting how DNA can help reveal ancient life history, says co-first author Kalle Leppl, a mathematical sciences researcher from Finlands University of Oulu. Gene flow direction is harder to determine than merely its presence, but these patterns are vital to understanding how past adaptations have transferred among species to give modern animals their current features.

The genomes included several new ones from Alaska, where both species are found. Also analysed was a new, more complete ancient polar bear genome. DNA was extracted from a tooth attached to a subfossil (not fully fossilised) jawbone found in Norways Svalbard archipelago. The bear would have lived 115,000 to 130,000 years ago.

Cowman was particularly impressed with the inclusion of the subfossils genome in the study, which he says is very rare.

Normally we analyse contemporary genetic samples from living species, living lineages, whereas here theyve managed to include an ancestral, a fossil lineage. And it really highlights how speciation is on a continuum.

Its not just a switch where two populations, over a certain amount of time, become separate species overnight. It really shows that they can interact and when they do come back into contact, there is the possibility for the sharing of genetic material.

Gene flow direction is harder to determine than merely its presence, but these patterns are vital to understanding how past adaptations have transferred among species to give modern animals their current features.

Im quite jealous! Ive got a background in studying fish and corals, and it would be nigh on impossible to get similar data from a fossil fish! This comes with the advances that were seeing in these genetic methods.

Being able to get viable DNA material from a fossil 10 years ago would have been nearly unheard of. Its not just these fossils that can be analysed think of all of the specimens in museums that are preserved in formalin or new preservation techniques. Getting ancestral DNA is a new field and revolutionised how we study these patterns of speciation.

Using the expanded dataset, the team estimated that polar bears and brown bears began to separate into distinct species between 1.3 and 1.6 million years ago. Lindqvist says that interbreeding and limited fossil evidence have made this timing hard to pinpoint.

Polar bears, soon after becoming a separate species, saw a dramatic decline in numbers, leading to a prolonged genetic bottleneck. The new research suggests that this has led to much less genetic diversity than is seen in brown bears.

The researchers found a remarkably similar story between the bear species as that between modern humans and Neanderthals. Their analysis found evidence of hybridisation in the genomes of both polar bears and brown bears. The influx of genetic information from the other species is particularly strong in polar bears. Earlier research suggested this was the other way around.

The team believes its findings may be of interest in studies concerned with the impact of climate change on threatened species.

Polar bears, adapted to the icy Arctic north, have been found to capture genetic material from brown bears, which are adapted to life in lower, warmer latitudes. As global warming sees a decline in Arctic sea ice, the two bear bears may intermingle more frequently as their ranges overlap. Lindqvist says this makes studying their shared evolutionary history all the more intriguing.

Population genomics is an increasingly powerful toolbox to study plant and animal evolution and the effects of human activity and climate change on endangered species, says team leader Luis Herrera-Estrella, from Mexicos National Laboratory of Genomics for Biodiversity and Texas Tech University in the US. Bears dont provide simple speciation stories any more than human evolution has. This new genomic research suggests that mammalian species groups can hide complicated evolutionary histories.

The implications of the results are that this ancestral polar bear lineage may have been able to get some novel gene from this expanding boreal brown bear and potentially that helped it to adapt to a changing climate, says Cowman. And the implication is that if its done it once, it can do it again.

That has implications across a lot of other species. But I think its important to understand that were using the past to try to predict the future a lot here. But it shows that there is this interaction between species and it can have all these different outcomes that we may not expect.

Cowman believes the techniques displayed in the PNAS paper are reflective of a development in our ability to delve into these problems of speciation, though he suggests that speciation remains an unsolved mystery. I guarantee you if one day, scientists did unite under a common or universal species concept, nature and evolution would say hold my beer and show us something completely different, he says. I think for me, thats the beauty of it all. Its so much fun, and it can be frustrating at times, to study evolution and speciation.

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Uncovering the mystery of speciation in bears - Cosmos

Summary: The absence of the NCX3 gene amplifies pain signals within the spinal cord, a new mouse study reveals. Increasing levels of NCX3 in the spinal cord helped reduce symptoms associated with chronic pain.

Source: University of Oxford

Oxford researchers have discovered a gene that regulates pain sensitization by amplifying pain signals within the spinal cord, helping them to understand an important mechanism underlying chronic pain in humans and providing a new treatment target.

Chronic pain is a common issue affecting millions of people worldwide, but why some people are more prone to it and what factors lead tochronic painare not fully understood.

It is well known that repeated stimulation, such as with a sharp pin prick, can lead to a heightened sensitivity to pain. This process is called pain wind-up and contributes to clinical pain disorders.

In a two-part study, researchers from Oxfords Nuffield Department of Clinical Neurosciences first comparedgenetic variationin samples from more than 1,000 participants from Colombia, to look for clues as to whether there were any genetic variants more common in people who experienced greater pain wind-up. They noted a significant difference in variants of one specific gene (the protein Sodium Calcium exchanger type-3, NCX3).

The researchers then undertook a series of experiments in mice, to understand how NCX3 regulates pain wind-up and whether it may be a treatment target. NCX3 was expressed in the mousespinal cordneurons that process and transmitpain signalsto the brain.

NCX3 was needed by these neurons to export the excess calcium that builds up following activity. In the absence of NCX3 the spinal cord neurons showed more activity in response to injury signals from the periphery and pain wind-up was increased.

Conversely, increasing the levels of NCX3 within the spinal cord could reduce pain in the mouse.

David Bennett, professor of neurology and neurobiology of the Nuffield Department of Clinical Neuroscience, said: This is the first time that we have been able to study pain in humans and then to directly demonstrate the mechanism behind it in mice, which provides us with a really broad understanding of the factors involved and how we can begin developing new treatments for it.

Professor Bennett added: Chronic pain is a global problem, and can be immensely debilitating. We carried out the study in Colombia because of the mixed ancestry of the population there, including Native Indian, African and European populations, which gave us a broad range of genetic diversity to look at. This makes these findings so exciting because of their potential international applications.

The findings imply that any drugs which can increase activity of NCX3 would be predicted to reducepainsensitization in humans.

Author: Press OfficeSource: University of OxfordContact: Press Office University of OxfordImage: The image is in the public domain

Original Research: Open access.Sodium-calcium exchanger-3 regulates pain wind-up: From human psychophysics to spinal mechanisms by Teodora Trendafilova et al. Neuron

Abstract

Sodium-calcium exchanger-3 regulates pain wind-up: From human psychophysics to spinal mechanisms

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is wind-up, in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation.

To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association withSLC8A3encoding sodium-calcium exchanger type 3 (NCX3).NCX3was expressed in mouse dorsal horn neurons, and mice lackingNCX3showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury.

Dorsal horn neurons lackingNCX3showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression ofNCX3reduced central sensitization.

Our study highlights Ca2+efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.

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Discovery of Gene Involved in Chronic Pain Creates New Treatment Target - Neuroscience News