Do stem-cell transplants increase cancer risk? Long-lived recipients offer clues


Ever since the first blood-forming stem cells were successfully transplanted into people with blood cancers more than 50 years ago, researchers have wondered whether they developed cancer-causing mutations. A unique study1 on the longest-lived transplant recipients and their donors has revealed that people who receive donor stem cells don’t seem to have an increased risk of developing such mutations.

The results are surprising but reassuring, says Michael Spencer Chapman, a haematologist at the Barts Cancer Institute in London.

“It’s fantastic news for people undergoing these therapies,” says Alejo Rodriguez-Fraticelli, a quantitative stem-cell biologist at the Institute for Research in Biomedicine in Barcelona, Spain.

Blood-forming, or ‘haematopoietic’, stem cells are precursor cells that reside in the bone marrow and give rise to all types of blood cell. They have been used to treat hundreds of thousands of people with blood cancers and bone-marrow diseases. The transplants involve depleting a person’s entire blood stem-cell reserves and replacing them with cells from a healthy donor. But researchers have long worried that putting the cells under such pressure could increase the risk of cancer. In rare cases, about 1 in every 1,000 transplants, donor cellsdevelop into a cancer in the recipients.

Fishing expedition

The latest study, published in Science Translational Medicine this week, looked at mutations in specific genes that have been linked to cancer. It was thought that these mutations could give haematopoietic cells a growth advantage in transplant recipients, allowing them to rapidly divide and multiply as the recipient ages and eventually develop into leukaemia.

Some of the first transplants were conducted at the Fred Hutchinson Cancer Center starting in the late 1960s. In 2017, Masumi Ueda Oshima, a clinical researcher who studies post-transplant ageing at the Fred Hutchinson Cancer Center in Seattle, Washington, and her colleagues decided to reach out to the recipients of these transplants, and their donors, to collect samples of their blood and compare how the cells had aged. “It was really a big fishing expedition,” she says.

The team collected blood samples from 32 individuals — 16 donor–recipient pairs — who had received their transplants between 7 and 46 years ago. They used a highly sensitive technique to sequence genes known to acquire mutations associated with bone-marrow cancers.The team found cells with mutations in all the healthy donors, even those as young as 12 years old. The older the donor, the mutations were present in their blood, but overall the frequency remained low — just one in a million of the sequenced base pairs.

The researchers then compared mutation patterns in 11 donor–recipient pairs for which they could access donor blood samples from the time of the transplant. They found similar mutation patterns in both groups. On average, mutations occurred at a rate of 2% per year in donors, and 2.6% per year in recipients. “Surprisingly, there actually are very few new mutations in the stem cells arising through the transplant process,” says Spencer Chapman. That suggests transplant recipients’ cells age at a similar rate to those in their donors, and they don’t have an increased risk of developing mutations, which might predispose them to blood cancers.

The fact that the mutations remain stable for so long after a transplant shows that “the regenerative capacity of the hematopoietic system is really profound”, says Ueda Oshima.

Rodriguez-Fraticelli says that although the results are comforting, they are based on a small number of individuals, which makes it difficult to draw broad conclusions.

Complex ageing

Spencer Chapman observed similar results in a separate study of donor–recipient pairs2, which was been posted online as a preprint in April 2023. His study included 10 transplant recipients who received haematopoietic cells from their siblings between 9 and 31 years earlier. But they didn’t just look for changes in specific genes associated with cancer, instead they extracted and grew haematopoietic cells in a dish and sequenced the entire genomes of individual cells. On average, they found that recipients had only slightly more mutations than their donors, adding just 1.5 years of normal ageing — a similar finding to Ueda Oshima’s.

When he and his colleagues looked specifically at mutations known to give cells a growth advantage, they noticed that cells that had only one of these mutations were found at similar levels in recipients and donors. But cells with two or more of these advantageous mutations were present at higher levels in recipients than donors. The result could help to explain why in rare cases, transplanted cells can develop into tumours.

But more work is needed to better understand the implications of these ageing processes, in terms of cancer risk and immune function, says Spencer Chapman.

Both studies could have implications for people receiving stem-cell transplants and blood-based gene therapies to treat sickle-cell disease, for example. More of these therapies are “hitting the mainstream” and being given to children, who will need to rely on the transplanted cells for the rest of their lives, says Spencer Chapman.

Scientists can reverse brain aging in fruit flies by preventing buildup of a common protein




Humans aren't the only ones who grow forgetful as they age -- fruit flies do, too. But because fruit flies have a lifespan of only about two months, they can be a useful model for understanding the cognitive decline that comes with aging.


A new study published in Nature Communications shows that when a common cell structural protein called filamentous actin, or F-actin, builds up in the brain, it inhibits a key process that removes unnecessary or dysfunctional components within cells, including DNA, lipids, proteins and organelles. The resulting accumulation of waste diminishes neuronal functions and contributes to cognitive decline. By tweaking a few specific genes in aging fruit flies' neurons, the researchers prevented F-actin buildup, maintained cellular recycling and extended the healthy lifespan of fruit flies by approximately 30%.

Actin, a family of proteins that help give cells their shape, are abundant throughout the body. F-actin forms filaments that are essential for maintaining cell structure and many other functions. The researchers, led by former postdoctoral scholar Edward (Ted) Schmid in David Walker's lab, noticed F-actin buildup in the brains of aging fruit flies and wondered if it contributed to brain aging and overall loss of organismal health.

Their first clue of a correlation: Flies on a restricted diet both lived longer and had less F-actin buildup in their brains. Their second clue: When treated with a drug known to extend lifespan, called rapamycin, there was also less F-actin in the brains of aged flies.

"But that's correlation, not a direct demonstration that F-actin is detrimental to aging of the brain," said Walker, senior author and UCLA professor of integrative biology and physiology. "To get at causality, we turned to genetics."

Because the fruit fly genome is thoroughly mapped and understood, the group was able to target in aging fruit flies genes that are known to play important roles in the accumulation of actin filaments. That included a gene called Fhos, a member of a family of proteins known to elongate and organize actin filaments."When we reduced Fhos expression in aging neurons, it prevented the accumulation of F-actin in the brain," said Schmid, now an investigator at the Arkansas Biosciences Institute and assistant professor at Arkansas State University. "This really allowed us to expand our study because now, we had a direct way to target F-actin accumulation in the brain and study how it affects the aging process."

Even though the genetic intervention was targeted to just neurons, it improved the flies' overall health. They lived 25-30% longer, while showing signs of improved brain function as well as markers of improved health in other organ systems. Preventing F-actin accumulation protected cognitive function, which shows the buildup is driving age-onset cognitive decline.


"Flies get more forgetful as they age, and their ability to learn and remember declines in middle age, just like it does in people," Walker said. "If we prevent accumulation of F-actin, it helps the flies learn and remember when older -- which tells us the buildup is not benign."

Further investigation showed the F-actin was interfering with the body's "cellular garbage disposal system." Damaged or superfluous proteins and other components inside a cell are broken down in a process called "autophagy." Aging research has established that autophagy pathways become less active with age, but no one knew exactly why.

The new study shows that preventing F-actin accumulation led to much more active autophagy in the brains of aged fruit flies. The authors found that if they removed F-actin but also disabled autophagy, it did not slow aging: The primary mechanism by which F-actin drives brain aging appears to be by impairing autophagy. The researchers also showed that disrupting F-actin in aged brains can restore brain autophagy to youthful levels and reverse certain cellular makers of brain aging.

These findings may be good news for the elderly fruit flies with reduced F-actin in their brains. But it has not yet been demonstrated in humans, and developing interventions to prevent F-actin accumulation might prove more challenging. Still, the discovery directs researchers in a fruitful new direction for healthier aging in people.

"Most of us in the aging field are focused on moving beyond lifespan into what we call the healthspan," said Walker. "We want to help people enjoy good health and a high quality of life while extending the lifespan. Our study improved cognitive and gut function, activity level, and overall healthspan of fruit flies -- and offers hope for what we might be able to achieve in humans."

The research was funded by the National Institutes of Health's National Institute on Aging.

AI 'can stunt the skills necessary for independent self-creation': Relying on algorithms could reshape your entire identity without you realizing







The rise of artificial intelligence (AI) poses questions not just for technology and the expanded plethora of possibilities it brings, but for morality, ethics and philosophy too. Ushering in this new technology carries implications for health, law, the military, the nature of work, politics and even our own identities — what makes us human and how we achieve our sense of self.


"AI Morality" (Oxford University Press, 2024), edited by British philosopher David Edmonds, is a collection of essays from a "philosophical task force" exploring how AI will revolutionize our lives and the moral dilemmas it will trigger, painting an immersive picture of the reasons to be cheerful and the reasons to worry. In this excerpt, Muriel Leuenberger, a postdoctoral researcher in the ethics of technology and AI at the University of Zurich, focuses on how AI is already shaping our identities.


Her essay, entitled "Should You Let AI Tell You Who You Are and What You Should Do?" explains how the machine learning algorithms that dominate today's digital platforms — from social media to dating apps — may know more about us than we know ourselves. But, she posits, can we trust them to make the best decisions for us, and what does that mean for our agency?Your phone and its apps know a lot about you. Who you are talking to and spending time with, where you go, what music, games, and movies you like, how you look, which news articles you read, who you find attractive, what you buy with your credit card, and how many steps you take. This information is already being exploited to sell us products, services, or politicians. Online traces allow companies like Google or Facebook to infer your political opinions, consumer preferences, whether you are a thrill-seeker, a pet lover, or a small employer, how probable it is that you will soon become a parent, or even whether you are likely to suffer from depression or insomnia.With the use of artificial intelligence and the further digitalization of human lives, it is no longer unthinkable that AI might come to know you better than you know yourself. The personal user profiles AI systems generate could become more accurate in describing their values, interests, character traits, biases, or mental disorders than the user themselves. Already, technology can provide personal information that individuals have not known about themselves. Yuval Harari exaggerates but makes a similar point when he claims that it will become rational and natural to pick the partners, friends, jobs, parties, and homes suggested by AI. AI will be able to combine the vast personal information about you with general information about psychology, relationships, employment, politics, and geography, and it will be better at simulating possible scenarios regarding those choices.


So it might seem that an AI that lets you know who you are and what you should do would be great, not just in extreme cases, à la Harari, but more prosaically for common recommendation systems and digital profiling. I want to raise two reasons why it is not.
Trust

How do you know whether you can trust an AI system? How can you be sure whether it really knows you and makes good recommendations for you? Imagine a friend telling you that you should go on a date with his cousin Alex because the two of you would be a perfect match. When deciding whether to meet Alex you reflect on how trustworthy your friend is. You may consider your friend's reliability (is he currently drunk and not thinking clearly?), competence (how well does he know you and Alex, how good is he at making judgements about romantic compatibility?), and intentions (does he want you to be happy, trick you, or ditch his boring cousin for an evening?). To see whether you should follow your friend's advice you might gently interrogate him: Why does he think you would like Alex, what does he think you two have in common?This is complicated enough. But judgements of trust in AI are more complicated still. It is hard to understand what an AI really knows about you and how trustworthy its information is. Many AI systems have turned out to be biased — they have, for instance, reproduced racial and sexist biases from their training data — so we would do well not to trust them blindly. Typically, we can't ask an AI for an explanation of its recommendation, and it is hard to assess its reliability, competence, and the developer's intentions. The algorithms behind the predictions, characterizations, and decisions of AI are usually company property and not accessible by the user. And even if this information were available, it would require a high degree of expertise to comprehend it. How do those purchase records and social media posts translate to character traits and political preferences? Because of the much-discussed opacity, or "black box" nature of some AI systems, even those proficient in computer science may not be able to understand an AI system fully. The process of how AI generates an output is largely self-directed (meaning it generates its own strategies without following strict rules designed by the developers), and difficult or nearly impossible to interpret.
Create Yourself!

Even if we had a reasonably trustworthy AI, a second ethical concern would remain. An AI that tells you who you are and what you should do is based on the idea that your identity is something you can discover — information you or an AI may access. Who you really are and what you should do with your life is accessible through statistical analysis, some personal data, and facts about psychology, social institutions, relationships, biology, and economics. But this view misses an important point: We also choose who we are. You are not a passive subject to your identity — it is something you actively and dynamically create. You develop, nurture, and shape your identity. This self-creationist facet of identity has been front and centre in existentialist philosophy, as exemplified by Jean-Paul Sartre. Existentialists deny that humans are defined by any predetermined nature or "essence." To exist without essence is always to become other than who you are today. We are continually creating ourselves and should do so freely and independently. Within the bounds of certain facts — where you were born, how tall you are, what you said to your friend yesterday — you are radically free and morally required to construct your own identity and define what is meaningful to you. Crucially, the goal is not to unearth the one and only right way to be but to choose your own, individual identity and take responsibility for it.AI can give you an external, quantified perspective which can act as a mirror and suggest courses of action. But you should stay in charge and make sure that you take responsibility for who you are and how you live your life. An AI might state a lot of facts about you, but it is your job to find out what they mean to you and how you let them define you. The same holds for actions. Your actions are not just a way of seeking well-being. Through your actions, you choose what kind of person you are. Blindly following AI entails giving up the freedom to create yourself and renouncing your responsibility for who you are. This would amount to a moral failure.

Ultimately, relying on AI to tell you who you are and what you should do can stunt the skills necessary for independent self-creation. If you constantly use an AI to find the music, career, or political candidate you like, you might eventually forget how to do this yourself. AI may deskill you not just on the professional level but also in the intimately personal pursuit of self-creation. Choosing well in life and construing an identity that is meaningful and makes you happy is an achievement. By subcontracting this power to an AI, you gradually lose responsibility for your life and ultimately for who you are.
A very modern identity crisis

You may sometimes wish for someone to tell you what to do or who you are. But, as we have seen, this comes at a cost. It is hard to know whether or when to trust AI profiling and recommendation systems. More importantly, by subcontracting decisions to AI, you may fail to meet the moral demand to create yourself and take responsibility for who you are. In the process, you may lose skills for self-creation, calcify your identity, and cede power over your identity to companies and government. Those concerns weigh particularly heavy in cases involving the most substantial decisions and features of your identity. But even in more mundane cases, it would be good to put recommendation systems aside from time to time, and to be more active and creative in selecting movies, music, books, or news. This in turn, calls for research, risk, and self-reflection.Of course, we often make bad choices. But this has an upside. By exposing yourself to influences and environments which are not in perfect alignment with who you currently are you develop. Moving to a city that makes you unhappy could disrupt your usual life rhythms and nudge you, say, into seeking a new hobby. Constantly relying on AI recommendation systems might calcify your identity. This is, however, not a necessary feature of recommendation systems. In theory, they could be designed to broaden the user's horizon, instead of maximizing engagement by showing customers what they already like. In practice, that's not how they function.

This calcifying effect is reinforced when AI profiling becomes a self-fulfilling prophecy. It can slowly turn you into what the AI predicted you to be and perpetuate whatever characteristics the AI picked up. By recommending products and showing ads, news, and other content, you become more likely to consume, think, and act in the way the AI system initially considered suitable for you. The technology can gradually influence you such that you evolve into who it took you to originally be.

Paleontologists discover Colorado 'swamp dweller' that lived alongside dinosaurs


A team of paleontologists working near Rangely, Colorado, has uncovered a new (or, more accurately, very old) state resident -- a fossil mammal about the size of a muskrat that may have scurried through swamps during the Age of Dinosaurs.


The researchers, led by the University of Colorado Boulder's Jaelyn Eberle, published their findings Oct. 23 in the journal PLOS ONE.

Eberle and her colleagues named their discovery, which they identified from a piece of jawbone and three molar teeth, Heleocola piceanus. The animal lived in Colorado roughly 70 to 75 million years ago -- a time when a vast inland sea covered large portions of the American West. (Fittingly, "Heleocola" roughly translates to "swamp dweller" in Latin)."Colorado is a great place to find fossils, but mammals from this time period tend to be pretty rare," said Eberle, curator of fossil vertebrates at the CU Museum of Natural History and professor in the Department of Geological Sciences. "So it's really neat to see this slice of time preserved in Colorado."

Compared to much larger dinosaurs living at the time like tyrannosaurs or the horned ancestors of Triceratops, the new fossil addition to Colorado might seem tiny and insignificant. But it was surprisingly large for mammals at the time, Eberle said.

She's also glad to see Rangely, which sits in the northwest corner of the state not far from Dinosaur National Monument, get its due.

"It's a small town, but, in my experience as a paleontologist, a lot of cool things come out of rural environments," Eberle said. "It's nice to see western Colorado have an exciting discovery."Land meets water


That cool discovery helps to paint a more complete picture of a Colorado that would be all but unrecognizable to residents today.

Paleontologists John Foster and ReBecca Hunt-Foster, co-authors of the new study, have been coming to this part of the state to dig up fossils every summer for about 15 years. Seventy million years ago, it was a place where land met water. Here, creatures like turtles, duck-billed dinosaurs and giant crocodiles may have flourished in and around marshes and estuaries, gorging themselves on wetland vegetation, fish and more.

"The region might have looked kind of like Louisiana," said ReBecca Hunt-Foster, a paleontologist at Dinosaur National Monument in Utah and western Colorado. "We see a lot of animals that were living in the water quite happily like sharks, rays and guitarfish."John Foster first remembers seeing the bit of mammal jaw emerge from a slab of sandstone that he collected from the site in 2016. The fossil measured about an inch long.

"I said, 'Holy cow, that's huge," said Foster, a scientist at the Utah Field House of Natural History State Park Museum in Vernal, Utah.

One big mammal

Eberle explained that before an asteroid killed off the non-avian dinosaurs 66 million years ago, mammals tended to be small -- most were about the size of today's mice or rats. She largely identifies them from the tiny teeth they left behind.H. piceanus, in comparison, was positively huge. Eberle estimates that the animal, a cousin to modern-day marsupials, weighed 2 pounds or more, larger than most Late Cretaceous mammals. (It's not quite a record -- another fossil mammal from the same period, known as Didelphodon, may have weighed as much as 11 pounds). Based on H. piceanus' teeth, the mammal likely dined on plants with a few insects or other small animals mixed in.

While dinosaurs get all the glory, the new find is another reason why paleontologists shouldn't overlook ancient mammals. Small or not, they played an important role in Colorado's ecosystems in the Late Cretaceous.

"They're not all tiny," Eberle said. "There are a few animals emerging from the Late Cretaceous that are bigger than what we anticipated 20 years ago."Hunt-Foster said that the Mountain West is a special place for anyone who loves fossils. She also urged people visiting public lands not to collect vertebrate fossils, such as dinosaurs, they may come across while hiking to avoid disturbing important scientific information. Instead, they should note the location, take a photo and alert a representative from a nearby museum or public land agency.

"We have scientists that come from all over the world specifically to study our fossils," she said. "We really are lucky."

How do genes shape the structures in our brains? We studied 70,000 people and found new links to ADHD and Parkinson’s

Brisbane, The human brain is a marvel of complexity. It contains specialised and interconnected structures controlling our thoughts, personality and behaviour.The size and shape of our brains also play a crucial role in cognitive functions and mental health. For example, a slightly smaller hippocampus, the structure responsible for regulation of memory and emotion, is commonly seen in depression. In dementia, atrophy of the hippocampus is correlated with memory loss and cognitive decline.Despite these insights, we have only scratched the surface of understanding the brain and its connection to mental health.

In collaboration with scientists around the world, we have conducted the world’s largest genetic study of the volume of regional structures of the brain. This study is now published in Nature Genetics.

We discovered hundreds of genetic variants that influence the size of structures such as the amygdala , the hippocampus and the thalamus .We uncovered their potential overlap with genes known to influence the risk of certain developmental, psychiatric and neurological disorders.

More than 70,000 brainsTo understand how the brain connects to mental health, scientists like ourselves engage in large-scale scientific studies that span the globe.

These studies, which involve thousands of volunteers, are the bedrock of modern biomedical research. They help us discover genes associated with brain size and mental health conditions. In turn, this can improve diagnostic precision and even pave the way for personalised medicine, which uses a person’s genetic test results to tailor treatments.

We screened the DNA and closely examined magnetic resonance imaging scans from more than 70,000 people across 19 countries. We wanted to find out if there are specific genetic variants influencing differences in brain sizebetween individuals.What we found was stunning. Some of these genes seem to act early in life, and many genes also increase the risk for conditions like attention-deficit hyperactivity disorder and Parkinson’s disease.

What did we find out?

Brain-related disorders are common, with an estimated 40% of Australians experiencing a mental health disorder in their lifetime.Our genetic findings reveal that larger regional brain volumes are associated with a higher risk of Parkinson’s disease. In comparison, smaller regional brain volumes are statistically linked with a higher risk of ADHD.

These insights suggest that genetic influences on brain size are fundamental to understanding the origins of mental health disorders. And understanding these genetic links is crucial. It shows how our genes can influence brain development and the risk of mental health conditions.By investigating shared genetic causes, we could one day develop treatments that address multiple conditions simultaneously, providing more effective support for individuals with various conditions. This is especially important in mental health, where it is common for someone to experience more than one disorder at the same time.

Our study also revealed that genetic effects on brain structure are consistent across people from both European and non-European ancestry. This suggests that certain genetic factors have stuck around throughout human evolution.

Bridging the gapsOur research also lays the groundwork for using genetic data to develop statistical models that predict disease risk based on a person’s genetic profile.

These advancements could lead to population screening, identifying those at higher risk for specific mental health disorders. Early intervention could then help prevent or delay the onset of these conditions.In the future, our goal is to bridge the gaps between genetics, neuroscience, and medicine. This integration will help scientists answer critical questions about how genetic influences on brain structure affect behaviour and disease outcomes.

Understanding the genetics of brain structure and mental health susceptibility can help us better prevent, diagnose and treat these conditions.

The concept of the “human brain” first appeared in ancient Greece around 335 BCE. The philosopher Aristotle described it as a radiator that prevented the heart from overheating. While we now know Aristotle was wrong, the complexities of the brain and its links to mental health remain largely mysterious even today.

As we continue to unlock the genetic secrets of the brain, we move closer to unravelling these mysteries. This type of research has the potential to transform our understanding and treatment of mental health. NSA

Researchers flip genes on and off with AI-designed DNA switches


Researchers at The Jackson Laboratory (JAX), the Broad Institute of MIT and Harvard, and Yale University, have used artificial intelligence to design thousands of new DNA switches that can precisely control the expression of a gene in different cell types. Their new approach opens the possibility of controlling when and where genes are expressed in the body, for the benefit of human health and medical research, in ways never before possible.


"What is special about these synthetically designed elements is that they show remarkable specificity to the target cell type they were designed for," said Ryan Tewhey, PhD, an associate professor at The Jackson Laboratory and co-senior author of the work. "This creates the opportunity for us to turn the expression of a gene up or down in just one tissue without affecting the rest of the body."In recent years, genetic editing technologies and other gene therapy approaches have given scientists the ability to alter the genes inside living cells. However, affecting genes only in selected cell types or tissues, rather than across an entire organism, has been difficult. That is in part because of the ongoing challenge of understanding the DNA switches, called cis-regulatory elements (CREs), that control the expression and repression of genes.

In a paper published in Oct. 23 advanced online issue of Nature, Tewhey and his collaborators not only designed new, never-before-seen synthetic CREs, but used the CREs to successfully activate genes in brain, liver or blood cells without turning on those genes in other cell types.Tissue- and time-specific instructions

Although every cell in an organism contains the same genes, not all the genes are needed in every cell, or at all times. CREs help ensure that genes needed in the brain are not used by skin cells, for instance, or that genes required during early development are not activated in adults. CREs themselves are not part of genes, but are separate, regulatory DNA sequences -- often located near the genes they control.

Scientists know that there are thousands of different CREs in the human genome, each with slightly different roles. But the grammar of CREs has been hard to figure out, "with no straightforward rules that control what each CRE does," explained Rodrigo Castro, PhD, a computational scientist in the Tewhey lab at JAX and co-first author of the new paper. "This limits our ability to design gene therapies that only effect certain cell types in the human body."

"This project essentially asks the question: 'Can we learn to read and write the code of these regulatory elements?'" said Steven Reilly, PhD, assistant professor of genetics at Yale and one of the senior authors of the study. "If we think about it in terms of language, the grammar and syntax of these elements is poorly understood. And so, we tried to build machine learning methods that could learn a more complex code than we could do on our own."Using a form of artificial intelligence (AI) called deep learning, the group trained a model using hundreds of thousands of DNA sequences from the human genome that they measured in the laboratory for CRE activity in three types of cells: blood, liver and brain. The AI model allowed the researchers to predict the activity for any sequence from the almost infinite number of possible combinations. By analyzing these predictions, the researchers discovered new patterns in the DNA, learning how the grammar of CRE sequences in the DNA impact how much RNA would be made -- a proxy for how much a gene is activated.

The team, including Pardis Sabeti, MD, DPhil, co-senior author of the study and a core institute member at the Broad Institute and professor at Harvard, then developed a platform called CODA (Computational Optimization of DNA Activity), which used their AI model to efficiently design thousands of completely new CREs with requested characteristics, like activating a particular gene in human liver cells but not activating the same gene in humanblood or brain cells. Through an iterative combination of 'wet' and 'dry' investigation, using experimental data to first build and then validate computational models, the researchers refined and improved the program's ability to predict the biological impact of each CRE and enabled the design of specific CREs never before seen in nature.

"Natural CREs, while plentiful, represent a tiny fraction of possible genetic elements and are constrained in their function by natural selection," said study co-first author Sager Gosai, PhD, a postdoctoral fellow in Sabeti's lab. "These AI tools have immense potential for designing genetic switches that precisely tune gene expression for novel applications, such as biomanufacturing and therapeutics, that lie outside the scope of evolutionary pressures."

Pick-and-choose your organTewhey and his colleagues tested the new, AI-designed synthetic CREs by adding them into cells and measuring how well they activated genes in the desired cell type, as well as how good they were at avoiding gene expression in other cells. The new CREs, they discovered, were even more cell-type-specific than naturally occurring CREs known to be associated with the cell types."The synthetic CREs semantically diverged so far from natural elements that predictions for their effectiveness seemed implausible," said Gosai. "We initially expected many of the sequences would misbehave inside living cells."

"It was a thrilling surprise to us just how good CODA was at designing these elements," said Castro.


Tewhey and his collaborators studied why the synthetic CREs were able to outperform naturally occurring CREs and discovered that the cell-specific synthetic CREs contained combinations of sequences responsible for expressing genes in the target cell types, as well as sequences that repressed or turned off the gene in the other cell types.Finally, the group tested several of the synthetic CRE sequences in zebrafish and mice, with good results. One CRE, for instance, was able to activate a fluorescent protein in developing zebrafish livers but not in any other areas of the fish.

"This technology paves the way toward the writing of new regulatory elements with pre-defined functions," said Tewhey. "Such tools will be valuable for basic research but also could have significant biomedical implications where you could use these elements to control gene expression in very specific cell types for therapeutic purposes."

Brain stimulation at home helps to treat depression






A remote clinical trial involving more than 150 people has shown that an experimental treatment for depression — which uses a swimming-cap-like device to gently stimulate the brain — can be effective when carried out at home.

The non-invasive therapy, known as transcranial direct current stimulation (tDCS), is designed to stimulate areas of the brain linked to mood regulation, and delivers a painless, weak electrical current through electrodes placed on the scalp. It could be a game-changer for the more than one-third of people with depression who do not respond to standard treatments such as antidepressants or  psychotherapy.

How deep brain stimulation is helping people with severe depression

The trial, described on 21 October in Nature Medicine1, found that after ten weeks of regular treatment, participants who received tDCS showed a greater reduction in depressive symptoms than did those in a control group. Previous research has explored using tDCS to treat depression, but this study stands out for its long timescale and remote, home-based design, which did not require participants to make daily visits to a specialized clinic.“When we think about that aspect of barriers to mental health, accessibility is a huge one,” says Shawn McClintock, a clinical neuropsychologist at UT Southwestern Medical Center in Dallas, Texas, who was not involved in the study. The trial “really starts to substantiate the ability to take mental health treatments into a home setting”, he adds.
Making brain cells fire

In the trial, researchers targeted the dorsolateral prefrontal cortex, a region of the brain involved in decision-making that is often less active in people with depression. “The tDCS involves a small current that makes it easier for the brain cells to discharge or to fire,” says study co-author Cynthia Fu, a clinical neuroscientist at King’s College London.

Fu and her colleagues trained 120 women and 54 men, all of whom had been diagnosed with a major depressive disorder, to use the tDCS headset and randomly allocated people to either the treatment or a control group.

Found: a brain-wiring pattern linked to depression

Those in the treatment group received a current of 2 milliamperes to the scalp — about 0.5% of the amount drawn by a 100-watt light bulb — for 30 minutes, 5 times a week for thefirst 3 weeks, then 3 times a week for 7 weeks. Participants in the control group wore a sham headset, which only delivered a brief pulse of current at the start of each session, mimicking the feeling of real tDCS without providing the same stimulation.

After 10 weeks, the treatment group’s scores on a scale that measures depression symptoms dropped by 9.41 points, whereas the control group’s score decreased by 7.14 points. Nearly 45% of participants with the active tDCS device experienced reduction in or recovery from their symptoms, compared with almost 22% of those with sham device. The headsets were used in addition to other treatments — many of the study participants took antidepressants and enrolled in psychotherapy for at least six weeks prior to the study.
Mixed results

Although these results are encouraging, previous research has suggested that tDCS doesn’t work for everyone. Last year, for example, a study of 150 people found that tDCS did not have antidepressant effects2. But trials with positive and negative outcomes are both equallyimportant to investigate the method’s potential as a treatment for depression, says Frank Padberg, a psychiatrist at Ludwig Maximilian University in Munich, Germany. The next step should be to understand why tDCS works for some people but not others, and to look for ways to personalize the treatment, he adds. “Different people need different dosages.”

Future studies could also use brain imaging and electrical recording to observe changes in neural circuits during tDCS treatment in real time, says McClintock. This would help researchers to “see what this treatment is actually doing at the neural circuit level”.

“Three decades ago, I wouldn't have thought that this stimulation does anything on the brain,” says Padberg. But now it is known that tDCS affects brain activity, “I'm pretty sure that an optimized method will make it to clinical care one day,” he says.

Global carbon dioxide emissions from forest fires increase by 60 percent


A major new study reveals that carbon dioxide (CO2) emissions from forest fires have surged by 60% globally since 2001, and almost tripled in some of the most climate-sensitive northern boreal forests.


The study, led by the University of East Anglia (UEA) and published today in Science, grouped areas of the world into 'pyromes' -- regions where forest fire patterns are affect`ed by similar environmental, human, and climatic controls -- revealing the key factors driving recent increases in forest fire activity.

It is one of the first studies to look globally at the differences between forest and non-forest fires, and shows that in one of the largest pyromes, which spans boreal forests in Eurasia and North America, emissions from fires nearly tripled between 2001 and 2023.



Significant increases were seen more broadly across the extratropical forests and amounted to an additional half a billion tonnes of CO2 per year, with the epicentre of emissions shifting away from tropical forests and towards the extratropics.

Increased emissions were linked to a rise in fire-favourable weather, such as the hot-dry conditions seen during heatwaves and droughts, as well as increased rates of forest growth creating more vegetation fuels. Both trends are aided by rapid warming in the high northern latitudes, which is happening twice as fast as the global average.

The study reveals a worrying increase in not only the extent of forest wildfires over the last two decades, but also their severity. The carbon combustion rate, a measure of fire severity based on how much carbon is emitted per unit of area burned, increased by almost 50% across forests globally between 2001 and 2023.The work involved an international team of scientists -- from the UK, the Netherlands, US, Brazil, and Spain -- who warn that further expansion of forest fires can only be averted if the primary causes of climate change, such as fossil fuel emissions, are tackled.


Lead author Dr Matthew Jones, of the Tyndall Centre for Climate Change Research at UEA, said: "Increases in both the extent and severity of forest fires have led to a dramatic rise in the amount of carbon emitted by forest fires globally. Startling shifts in the global geography of fires are also underway, and they are primarily explained by the growing impacts of climate change in the world's boreal forests.

"To protect critical forest ecosystems from the accelerating threat of wildfires, we must keep global warming at bay and this underscores why it is so vital to make rapid progress towards net zero emissions."Threats to carbon storage

Forests are of worldwide importance for carbon storage, with their growth helping to remove CO2 from the atmosphere and reduce rates of global warming. They also play a crucial role in meeting international climate targets, with reforestation and afforestation schemes being implemented to remove carbon from the atmosphere and offset human CO2 emissions from hard-to-abate sectors such as aviation and certain industries.


"Until now, reduced burning in the already fire-prone savannahs and grasslands has masked increases in forest fire extent and severity that are hugely consequential for society and the environment," said Dr Jones. "Our work shows that fires are increasingly happening where we don't want them to -- in forests, where they present the greatest threat to people and to vital carbon stores."Managing wildfires

Machine learning was key to unlocking new observations about the shifting global geography of forest fires. It was used to group the world's forest ecoregions into 12 distinct pyromes, allowing the researchers to isolate the effects of climate change from other influencing factors such as land use.

This knowledge also reveals new insights into which strategies can be most effective for mitigating wildfires and protecting forests. Dr Jones said: "Substantial financing is required to support strategic programs of forest management, stakeholder engagement, and public education, all of which represent a meaningful shift of fire management strategy from largely reactive to increasingly proactive."For example, priority areas for forest management and fire breaks must be defined based on proactive monitoring of forest productivity, particularly in the extratropics. Managing fuel loads in places where they could present greatest danger during fire-favourable weather is a key priority for limiting the severity and impact of fires when they do occur." The work was supported by funders including the UK Natural Environment Research Council (NERC), European Commission Horizon 2020 programme, and European Space Agency.

The work was supported by funders including the UK Natural Environment Research Council (NERC), European Commission Horizon 2020 programme, and European Space Agency.The success of these schemes relies on carbon being stored in forests permanently, and wildfires threaten that. Extratropical fires are already emitting half a billion tonnes more CO2 than two decades ago, and the long-term effect depends on how forests recover. More widespread and severe forest fires are a sign that emissions are now out of balance with the carbon captured by post-fire recovery.

Dr Jones, a NERC Independent Research Fellow, said: "The steep trend towards greater extratropical forest fire emissions is a warning of the growing vulnerability of forests and it poses a significant challenge for global targets to tackle climate change.


"We know that forests rebound poorly after the most severe fires, so there is huge interest in how the observed increases in fire severity will influence carbon storage in forests over the coming decades. This demands our close attention."

Escalating wildfire impacts masked until now

Significantly, the increased emissions from forest fires contrasts with the reduced burning of the world's tropical savannahs during the same period. Previous studies have shown that, since 2001, the area burned by all fires (forest and non-forest) fell by a quarter globally, mainly due to this.

The latest findings are important because forest fires burn more severely and release larger amounts of harmful smoke to the atmosphere than savannah grassland fires, presenting major threats to those living near fires and to more distant communities exposed to poor air quality caused by smoke.

The authors say the study debunks the narrative that falling overall annual area burned by fire globally means falling wildfire impact.

Archaeologists discover 12 skeletons at a buried tomb in Petra, Jordan



Archaeologists say they've made a remarkable discovery in a place already known for its rich ancient history: 12 full skeletons in a tomb beneath one of Jordan's biggest tourist attractions.

The remains were found beneath the Treasury, also called Al Khazneh, in the ancient city of Petra — famous as a landmark seen in the movie Indiana Jones and the Last Crusade.

The Treasury, believed to be a mausoleum, was carved by the Nabataean people around 2,000 years ago. Petra was the capital of the Nabataeans, who carved many elaborate structures out of rose-colored rock. The city is now a UNESCO World Heritage site.

Richard Bates, a professor of geophysics at the University of St Andrews in Scotland who was part of the archaeological team, said the discovery will help researchers learn more about the ancient people."If you look at all the other tombs in the Petra area, only a few have ever contained any human remains, and those are very fragmentary, whereas this has got 12 complete bodies within it," he told NPR.


Bates said the discovery not only sheds light on the rituals involved in Nabataean birth and death practices, but also, "by analyzing the skeleton material, the teeth, the bones, we can tell things about their lifestyle. So it's going to unlock a view on Nabataean life that we've just never had access to before."

A local archaeological team obtained the rare permission to get inside the Treasury building. Bates ran ground-penetrating radar as part of the team. "That's when we discovered the signals which I interpreted as voids in the subsurface," he said.


The new chamber is about 18 feet by 18 feet and 9 feet tall, he estimates, and preliminary dating puts it from around the first century B.C. to the first century A.D., in the middle of the Nabataean Kingdom. The civilization existed from roughly the 4th century B.C. until it was annexed by the Romans in 106 A.D.

THE TWO-WAY
Massive Structure Found 'Hiding In Plain Sight' At Ancient Site Of Petra

Archaeologists had already discovered indications of this tomb around 2003, but the dig site was shut down over lack of funding at the time, Bates said. Separate tombs were discovered at the Treasury in 2004, according to Petra's tourism authority, which says they were royal tombs.

The tomb's discovery happened over the summer but is now being publicized as part of the show Expedition Unknown on the Discovery Channel.




In a coincidence, the crew also found that one skeleton was holding a ceramic vessel similar to a famous chalice seen in the Indiana Jones movie.

Archaeologist Pearce Paul Creasman of the American Center of Research, who led the team, said in a press statement that mysteries still remain about the Treasury. "When was this remarkable structure built, and why? Little did we know that this dig might completely change what we know about The Treasury and help solve the mysteries of the Nabataean people."

In an email to NPR, Creasman also credits the work of the project's co-directors: Fadi Bala'awi, the director general of Jordan's Ministry of Tourism and Antiquities; and Fares Braizat, the chief commissioner of the Petra Development and Tourism Region Authority.

What happens next for the project comes down to funding.

"The next step for this set of discoveries is to get the money to properly exhume at least one of the bodies and do a full study on it," Bates said, with the goal of examining all the bodies.

How does the brain react to birth control? A researcher scanned herself 75 times to find out



Chicago, Illinois

Hold the morning coffee and meditation: for about 75 days over the span of a year, neuroscientist Carina Heller's morning ritual included climbing into her university's brain scanner at 7:30 a.m. and lying perfectly still for an hour and a half — without falling asleep. By her estimates, this has made her the most-scanned woman in science.

It’s not the title she was after. Heller’s goal was to catalogue how her brain changes during her menstrual cycle, with and without oral contraceptives . Her findings suggest that brain morphology and connectivity change daily throughout the natural cycle and are influenced by birth-control pills, according to preliminary results presented at this year’s annual Society for Neuroscience conference.

Heller is one of a cadre of women’s health researchers who are tired of waiting for data to trickle in on a chronically understudied area, and have taken matters into their own hands by hopping into a brain-imaging machine. More data could offer women and their physicians greater agency to make “better-informed decisions of whether they want to take the medication or not”, and what specific formulations might be best suited for them, says Heller, who is based at the University of Minnesota Twin Cities in Minneapolis.

“She did this rigorous self-experimentation where she gave herself up to science,” says Emily Jacobs, a neuroscientist at the University of California, Santa Barbara, who works with Heller.“And as a result, we now have this greater insight into the human brain.”


Research gaps

Oral contraceptives often contain synthetic versions of one or two hormones the body naturally produces: progesterone and oestrogen. These hormones prevent pregnancy in several ways, including by stopping the ovaries from releasing an egg.

US regulators approved the first oral contraceptive in 1960. Within two years, more than one million people were taking ‘the pill’, as it became known. Today, more than 150 million people of reproductive age globally take oral contraceptives, placing them among the most-used medications in the world. Many take the pill for reasons unrelated to conception, such as managing acne, regulating menstrual cycles or helping to relieve menstrual symptoms and migraines.

Decades of data on these medicines suggest that they are generally safe, but their effects on the brain remain understudied. For example, although some people report that they experience decreased depression and anxiety, others find that these symptoms worsen — and it’s unclear why.

Many people begin taking the pill during puberty, which is a crucial time for brain maturation, so it’s important to understand how it affects neurodevelopment, says Kathryn Lenz, a behavioural neuroscientist at The Ohio State University in Columbus.
The adaptable brain

Most neuroimaging experiments use magnetic resonance imaging (MRI) technology to scan the brains of 10–30 participants only once or twice, which is costly to perform. This approach fails to account for daily variation in brain morphology and connectivity.

A growing number of neuroimaging studies instead use a technique called ‘ dense sampling ’, in which researchers scan a single or handful of participants repeatedly to build a high-resolution data set. Dense sampling captures observations that might otherwise be overlooked, but the small sample size results in limited generalizability of findings to larger populations.

Even so, by comparing data sets between participants — especially those who have different reactions to the pill — researchers might be able to pinpoint what drives different side effects.

Using this approach, Heller scanned herself 25 times over 5 weeks, capturing images at different stages of her natural menstrual cycle. A few months later, she began taking oral contraceptives and then waited 3 months before scanning herself another 25 times in 5 weeks. At that point, Heller ceased taking the pill, waited another 3 months and scanned herself a final 25 times over 5 weeks. She also had blood drawn and completed a survey about her mood after each scan.

Heller found a rhythmic pattern of change in brain volume and connectivity between brain regions over the course of her menstrual cycle, with volume and connectivity dipping slightly while she was taking oral contraceptives. (Higher brain volume or connectivity does not imply improved brain function, and vice versa.)

This pattern largely returned to its former state after she stopped taking the medication, showing that the brain is “quite adaptable”, says Laura Pritschet, who conducted her graduate work with Jacobs and is now a cognitive neuroscientist at the University of Pennsylvania in Philadelphia.
An expanding network

Heller drew inspiration from a study in which Pritschet scanned her own brain for 30 consecutive days during her natural menstrual cycle and for 30 more days while taking oral contraceptives. This was part of a project that Pritschet calls 28andMe: the name is a nod to the consumer-genetics firm 23andMe in South San Francisco, California, and the 28 days in a canonical menstrual cycle.

Data from Pritschet’s project showed that higher levels of oestrogen drive certain important brain networks to become more functionally connected 1. One of these was the ‘default mode network’, which is active during daydreaming and is involved in memory. Progesterone had the opposite effect. Pritschet also scanned her husband over 30 consecutive days in a spin-off project called 28andHe, to understand the effects of hormone fluctuations in the male brain2.

Next, Heller plans to compare her data with those from a woman with endometriosis, a painful condition that affects up to 10% of reproductive age women, to understand whether hormone fluctuations in the brain could be driving the condition.

These data sets are “going to give us a really intriguing window into the relationship between hormonal status and subtle changes in brain structure and behavioural functions”, Lenz says.

ALS drug shows promise in targeting glioblastoma stem cells

Glioblastoma is the most common – and the most malignant – primary brain tumour in adults. It's aggressive and incurable. Even with treatment including surgical removal and chemotherapy, the median survival for patients is just 18 months.

Now, innovative new research led by Dr. Arezu Jahani-Asl, Canada Research Chair in Neurobiology of Disease at the University of Ottawa, provides highly compelling evidence that a drug used to slow the progression of the disease ALS shows promise in suppressing the self-renewing cancerous stem cells that challenge the present standards of care for these lethal grade 4 brain tumours.

Her team's findings could prove highly impactful because brain tumour stem cells (BTSCs) are at the very core of therapeutic resistance and tumour recurrence in glioblastoma, a devasting and treatment-resistant type of cancer that impacts four per 100,000 people in Canada.

Indeed, discovering ways to effectively target these rare populations of highly resistant cells could have major implications for global efforts to combat brain cancer, according to Dr. Jahani-Asl, associate professor in the Department of Cellular and Molecular Medicine and a member of the uOttawa Brain and Mind Institute.

Here's what the uOttawa-led team found: The drug edaravone (brand name Radicava) inhibits the self-renewal and proliferation of brain tumour stem cells so repurposing the drug may prove to be a potent weapon against glioblastoma. They reported their findings in the journal Stem Cell Reports.

"We show that edaravone specifically targets cancer stem cells and is particularly effective in combination with ionizing radiation," she says. "The study suggests that edaravone in combination with ionizing radiation can be effective in eradicating cancer stem cells, and thus is expected to decrease the chance of resistance to therapy and recurrence in glioblastoma patients."

Ionizing radiation is a type of radiation that is used in cancer therapy to kill or inhibit the growth of malignant cells. Next steps for the researchers include writing a protocol on the best ways to optimize edaravone drug dosage in combination with ionizing radiation and chemotherapy.

Repurposing existing marketed drugs already approved for human use is an increasingly popular strategy of battling different types of cancer cells. And compounds that have already been proven safe could potentially advance swiftly to clinical trials. Since edaravone is an approved compound that has already been shown safe in humans, Dr. Jahani-Asl says repurposing the drug and its translation for glioblastoma is "very promising."Edaravone was approved by the U.S. Food and Drug Administration in 2017 to treat ALS, and Health Canada approved the drug's oral formulation in 2022. It's also used to treat stroke.

Before the completed study provided compelling evidence that edaravone sensitizes glioblastoma tumours to radiation therapy in animal models, the research team conducted gene expression analysis in patient-derived brain tumour stem cells in the absence and presence of the drug.

"We found significantly deregulated gene panels related to stemness and DNA repair mechanisms which was the spark to begin a new major line of investigation," Dr. Jahani-Asl says.

Achieving new insights into BTSC regulation is at the forefront of efforts to battle glioblastoma, and Dr. Jahani-Asl is an international leader in this effort. Her research program at the uOttawa Faculty of Medicine is centered on developing novel therapeutic strategies for complex and devastating brain diseases.

Any new drug for glioblastoma is expected to be used in combination with the present standard treatments which includes ionizing radiation and chemotherapy.

"Our goal is now to try to optimize dosage for a safe therapeutic window," Dr. Jahani-Asl says. "Once we establish a dose that is safe for use in combination therapy, we will be well equipped with the knowledge to move this forward to clinic."

Bright night light exposure increases mortality risk, while daylight reduces it






In a recent study published in the journal Proceedings of the National Academy of Sciences, researchers investigated whether personal day and night light exposure and circadian rhythm disruption could predict the risk of mortality.


They found that exposure to brighter daytime light reduced mortality risk. In comparison, exposure to brighter nighttime light and disrupted circadian rhythms (low amplitude, early or late phase) increased mortality risk, particularly for cardiometabolic causes, which showed stronger associations than other causes.
Background

Disruption of the circadian rhythm is linked to various adverse health outcomes, including an increased risk of premature mortality. Nighttime light exposure shifts the timing and weakens the signal of the circadian pacemaker in the hypothalamus, leading to circadian disruption.

Animal studies show that exposure to light at night causes premature death, and human populations exposed to more night light, such as shift workers and evening types, have higher mortality risks.

While night light disrupts circadian rhythms, daylight stabilizes and strengthens them, potentially reducing sensitivity to night light and protecting against circadian-related health issues.

Studies suggest that daylight exposure lowers risks of all-cause mortality and cardiovascular diseases, though they often rely on self-reports or satellite data. Circadian disruption, particularly from irregular light exposure, is associated with cardiometabolic disorders like hypertension, diabetes, and heart disease.

However, there is a dearth of large-scale studies on personal light exposure and cardiometabolic mortality risks. Therefore, researchers in the present study investigated the potential association between day and night light, circadian rhythms, and mortality risk using ~13 million hours of personal light exposure data obtained from light sensors.
About the study

In the present study, ~89,000 participants from the United Kingdom (UK) Biobank wore wrist devices to track personal light exposure data over about seven days.

Light exposure data were collected at 100 Hz using a light sensor sensitive to human vision, and profiles were created based on half-hour intervals across the 24-hour day.

Participants with insufficient data or device issues were excluded, leaving 88,905 individuals. The mean age of the participants was 62.4 years, 56.9% of them were female, and 97% were White.

Mortality data, including those of all-cause, cardiometabolic-cause, and other-cause mortality, were collected from the National Health Service (NHS) Digital (England) and NHS Central Register (Scotland) over a mean follow-up period of eight years.

Baseline covariates like ethnicity, income, smoking, and physical activity were considered, along with photoperiod and sleep data. Cox proportional hazards models were used to estimate mortality risk, and light exposure percentiles were divided into day and night groups.

Circadian phase and amplitude were modeled using a computational approach, predicting the circadian disruption based on personal light exposure data. Z-scores of amplitude values and phase variability were included in the models.
Results and discussion

A total of 3,750 all-cause deaths and 798 cardiometabolic deaths were recorded. Exposure to brighter night light was found to be associated with increased all-cause mortality risk (adjusted hazard ratio [aHR] range: 1.15 to 1.34), with stronger associations for cardiometabolic mortality (aHR range: 1.22 to 1.46), and other-cause mortality (aHR range: 1.13 to 1.15).

On the other hand, exposure to brighter daylight was found to correlate with lower risks of all-cause mortality (aHR range: 0.66 to 0.90) and cardiometabolic mortality (aHR range: 0.61 to 0.84).

Individuals in higher night light percentiles showed significantly elevated risks compared to those in the darkest percentiles (0 to 50th). Additionally, lower circadian amplitude and both early and late circadian phases predicted higher mortality risks.

The study also found that short sleep (less than six hours) partially attenuated the association between night light and all-cause mortality. However, the impact of daylight exposure remained significant, regardless of sleep duration or efficiency.

Overall, the findings suggest that avoiding nightlight and seeking daylight may promote better health and longevity, offering an accessible and cost-effective recommendation for potentially improving well-being.

However, the study is limited by its reliance on only one week of light data, the computational model based on younger adults, and the lack of data on individual light sensitivity. There is also a limitation regarding the cohort's predominantly white ethnicity, which may affect generalizability.
Conclusion

In conclusion, the study suggests that maintaining darkness during late night and early morning, when circadian rhythms are most sensitive, and seeking bright light during the day can potentially enhance circadian function. This is especially important for those at risk of circadian disruption, such as in intensive or elderly-care settings.

Runaway stars could influence the cosmos far past their home galaxies



Dozens of fugitive stars were caught fleeing a dense star cluster in a satellite galaxy of the Milky Way. The swarm of speeding stars could mean that such runaways had a bigger influence on cosmic evolution than previously thought, astronomers report October 9 in Nature.

Massive stars are born in young clusters, packed so close together that they can jostle each other out of place. Sometimes, encounters between pairs of massive stars or neighboring supernova explosions can send a star zipping out of the cluster altogether, to seek its fortune in the wider galaxy and beyond.Astronomer Mitchel Stoop of the University of Amsterdam and his colleagues searched for runaway stars around a huge cluster of massive stars called Radcliffe 136 using data from the Gaia spacecraft on the speeds and positions of billions of stars (SN: 6/13/22). R136 is located about 170,000 light-years from Earth in the Large Magellanic Cloud, a dwarf galaxy that orbits the Milky Way.

The cluster “is an iconic object,” says astrophysicist Sally Oey of the University of Michigan in Ann Arbor, who was not involved in the new work. The view from Earth’s neighborhood is so clear, “we can really look at things up close and personal.”

Previous studies had found a few stars fleeing the cluster (SN: 5/7/10). But in a wider search, Stoop found an astonishing 55 stars had fled at speeds faster than roughly 100,000 kilometers per hour in the past 3 million years.“That is an incredible number to think about,” Stoop says. The observation suggests that as many as a third of the brightest, most massive stars born in the cluster have left home.

That means runaway stars could be an underappreciated force in the universe. These massive stars, about five to 140 times the mass of the sun, emit ultraviolet radiation and supersonic stellar winds that can sculpt the gas and dust around them (SN: 7/11/22). At the end of their lives, the heavyweight stars explode as supernovas, spreading heavy elements around the galaxy (SN: 7/7/21).

“Before, we’d expect maybe there are a handful of runaways,” Stoop says. But because of their presumed low numbers, he says, they would be left out of studies and simulations. If each cluster instead loses about a third of its stars to the surrounding galaxy, or even the space between galaxies, “they can maybe have a major contribution to dumping all these ultraviolet photons into the intergalactic medium.”Such escapees could also have had a profound influence on the evolution of the early universe. Within a few hundred million years of the Big Bang, more than 13 billion years ago, some source of ultraviolet radiation stripped electrons from a pervasive fog of hydrogen atoms, a phenomenon called reionization (SN: 11/7/19).

Astronomers think most of the photons, or particles of light, that cleared the cosmic fog came from dwarf galaxies (SN: 2/6/17). But simulations have found that only a fraction of the photons needed can escape the environments of those galaxies. Runaway stars could help account for the difference, Stoop says.

“Maybe this happened in [early universe] galaxies as well, during the epoch of reionization,” he says.Oey says, “There’s no doubt that runaway stars are really important and have been underappreciated.” But, she says, there are other ways to get ionizing radiation out of galaxies, and it’s not clear how much of a difference including runaway stars would make.The timing of the stars’ escape from R136 might also throw a wrench in the broader relevance of runaway stars to reionization.

Surprisingly, the stars didn’t all migrate in one wave. The scientists know this because they have the stars’ speeds and distances and can calculate when they started their escape. Most of the runaways fled R136 in all directions about 1.8 million years ago, when the cluster was forming. That’s what you’d expect if they were booted out by encounters with other massive stars.

But 16 of the escapees left the cluster more recently, just 200,000 or so years ago. And they were all fleeing in the same direction. Stoop and his colleagues think those stars’ escape might have been triggered by a merger with another cluster.

“That seems like a fairly unique occurrence,” says astrophysicist Kaitlin Kratter of the University of Arizona in Tucson. If R136’s double ejection is unusual, then it might be hard to extrapolate how many stars other clusters lose to their cosmic surroundings. Finding evidence of similar waves in other clusters would help resolve the question.

Europa Clipper begins epic journey to find what's hiding on Jupiter's moon

For decades, Europa has captivated not only scientists but also filmmakers, writers, and dreamers. This icy moon of Jupiter has played a starring role in science fiction, most famously in Arthur C. Clarke's 2010: Odyssey Two, where it is depicted as a world brimming with life.

Shrouded in ice, with a surface etched by cracks and mysterious ridges, this distant celestial body has long been a subject of fascination. What lies beneath its frozen exterior? Could its subsurface ocean, hidden several kilometres below, be the key to understanding life beyond Earth?The mission’s primary objective: to determine if Europa has the right conditions to support life.
WHAT IS EUROPA?

Europa, a moon around Jupiter, has intrigued the scientific community ever since the Galileo spacecraft first provided tantalising evidence of a global ocean beneath its icy shell in the 1990s.


The possibility of life existing in this remote, alien ocean has stirred imaginations ever since.

Unlike Earth, Europa’s ocean isn’t warmed by the sun, but by the tidal forces created by Jupiter’s immense gravitational pull. This process could generate the necessary heat to sustain microbial life in the dark depths of this hidden sea.
WHAT WILL EUROPA CLIPPER MISSION DO?

The Europa Clipper mission, with its $5 billion price tag and six-year journey, is NASA’s bold attempt to unravel these mysteries.

After travelling nearly 2.9 billion kilometres, the spacecraft will begin a series of 49 close flybys of Europa in 2030, conducting what may be the most detailed investigation ever undertaken of a celestial body beyond our planet.

Equipped with nine cutting-edge instruments, including ice-penetrating radar, cameras, and spectrometers, the spacecraft will delve deep into the moon’s icy crust and atmosphere, searching for signs that Europa’s ocean might harbour the essential building blocks of life.​


WHAT CAN BE EXPECTED?

The excitement around Europa Clipper stems from its potential to answer one of humanity’s oldest and most profound questions: Are we alone in the universe?

With each flyby, the spacecraft will scan Europa’s frozen landscape, measuring the thickness of the ice shell and looking for evidence of water plumes that might be venting from the ocean below.

These plumes, if confirmed, could provide a direct glimpse into the chemical makeup of Europa’s ocean, offering clues to its habitability.



Europa is thought to have more water than all of Earth’s oceans combined, locked away beneath its surface. If life can exist there, in complete darkness under miles of ice, it could fundamentally reshape our understanding of where life could thrive in the cosmos.​

In the years leading up to its arrival at Europa, the Europa Clipper’s journey will be watched closely by space enthusiasts around the globe. While it will take six years for the spacecraft to reach its destination, the mission promises to be a turning point in the quest to find life beyond Earth.



As the Europa Clipper hurtles through space toward its icy target, it carries with it the hopes and dreams of humanity, bound on a daring voyage to unlock the secrets of a distant moon that may hold answers to questions humans have pondered for centuries.

AI scans RNA ‘dark matter’ and uncovers 70,000 new viruses

Researchers have used artificial intelligence (AI) to uncover 70,500 viruses previously unknown to science1, many of them weird and nothing like known species. The RNA viruses were identified using metagenomics, in which scientists sample all the genomes present in the environment without having to culture individual viruses. The method shows the potential of AI to explore the ‘dark matter’ of the RNA virus universe.

Viruses are ubiquitous microorganisms that infect animals, plants and even bacteria, yet only a small fraction have been identified and described. There is “essentially a bottomless pit” of viruses to discover, says Artem Babaian, a computational virologist at the University of Toronto in Canada. Some of these viruses could cause diseases in people, which means that characterizing them could help to explain mystery illnesses, he says.

Previous studies have used machine learning to find new viruses in sequencing data. The latest study, published in Cell this week, takes that work a step further and uses it to look at predicted protein structures1. The AI model incorporates a protein-prediction tool, called ESMFold, that was developed by researchers at Meta (formerly Facebook, headquartered in Menlo Park, California). A similar AI system, AlphaFold, was developed by researchers at Google DeepMind in London, who won the Nobel Prize in Chemistry this week.
Missed viruses

In 2022, Babaian and his colleagues searched 5.7 million genomic samples archived in publicly available databases and identified almost 132,000 new RNA viruses2. Other groups have led similar efforts3.

But RNA viruses evolve quickly, so existing methods for identifying RNA viruses in genomic sequence data probably miss many. A common method is to look for a section of the genome that encodes a key protein used in RNA replication, called RNA-dependent RNA polymerase (RdRp). But if the sequence that encodes this protein in a virus is vastly different from any known sequence, researchers won’t recognize it.

Shi Mang, an evolutionary biologist at Sun Yat-sen University in Shenzhen, China, and a co-author of the Cell study, and his colleagues went looking for previously unrecognized viruses in publicly available genomic samples.They developed a model, called LucaProt, using the ‘transformer’ architecture that underpins ChatGPT, and fed it sequencing and ESMFold protein-prediction data. They then trained their model to recognize viral RdRps and used it to find sequences that encoded these enzymes — evidence that those sequences belonged to a virus — in the large tranche of genomic data. Using this method, they identified some 160,000 RNA viruses, including some that were exceptionally long and found in extreme environments such as hot springs, salt lakes and air. Just under half of them had not been described before. They found “little pockets of RNA virus biodiversity that are really far off in the boonies of evolutionary space”, says Babaian.


“It’s a really promising approach for expanding the virosphere,” says Jackie Mahar, an evolutionary virologist at the CSIRO Australian Centre for Disease Preparedness in Geelong. Characterizing viruses will help researchers to understand the microbes’ origins and how they evolved in different hosts, she says.


And expanding the pool of known viruses makes it easier to find more viruses that are similar, says Babaian. “All of a sudden you can see things that you just weren’t seeing before.”


The team wasn’t able to determine the hosts of the viruses they identified, which should be investigated further, says Mahar. Researchers are particularly interested in knowing whether any of the new viruses infect archaea, an entire branch of the tree of life for which no RNA viruses have been clearly shown to infect.


Shi is now developing a model to predict the hosts of these newly identified RNA viruses. He hopes this will help researchers to understand the roles that viruses have in their environmental niches.

Europa Clipper is launching to solve an alien mystery


NASA’s Europa Clipper spacecraft will soon be on its way to help solve a quarter-century-old mystery: Could anything live in the ocean that lurks beneath the icy shell of Jupiter’s moon Europa?

“This is a mission we’ve been dreaming of for 25 years now, since I was in graduate school,” says planetary geologist Cynthia Phillips of NASA’s Jet Propulsion Laboratory in Pasadena, Calif. “It’s a generational mission.”

An October 10 launch from Kennedy Space Center in Florida has been scrubbed due to Hurricane Milton, but the spacecraft is still expected to launch later this month or in early November.After a five-and-a-half-year trek to Jupiter, Clipper will settle into orbit around the giant planet in April 2030, repeatedly zipping past the icy moon to get snapshots of its frozen terrain, measure the chemical composition of the surface and deduce the moon’s internal structure.

“We think that ocean worlds might actually be a common type of world outside of our solar system,” said NASA’s head of planetary science Gina DiBraccio in a September 17 news conference. “Clipper will be the first in-depth mission that will allow us to characterize habitability on what could be the most common type of inhabited world in our universe.”

Planetary scientists have grown increasingly certain that Europa hosts a subsurface ocean ever since NASA’s Galileo spacecraft visited Jupiter in the 1990s (SN: 2/18/02).“During the Galileo mission, it was like a detective story,” Phillips says. The clues built up. A lack of craters, suggesting the surface is always moving and changing. Stripes, cracks and pits, suggesting upwelling from below. Regions known as “chaos terrain,” that look like icebergs tilted in a sloshy sea (SN: 11/16/11).

And finally, the measurement of an internal magnetic field induced by Jupiter’s external one. That was “the coup de grâce,” Phillips says. The only geologically plausible material capable of carrying that magnetic field is saltwater.

On Earth, water means life. But the findings on Europa weren’t enough to declare it a habitable world (SN: 4/19/24). Many mysteries remained: How deep is the ocean? How thick is the ice shell? And crucially, how do they interact? Could material from the surface make it down into the briny deep, to provide food for waiting microbes?Europa Clipper, named for the speedy clipper ships of the 19th century, is poised to pick up where Galileo left off. The spacecraft is charged with investigating Europa’s habitability by searching for three key ingredients: water, energy and organic compounds.

The spacecraft won’t orbit Europa directly. The moon lies within Jupiter’s punishing radiation environment, where high-energy charged particles accelerated by the planet’s magnetic field could fry spacecraft components (SN: 11/9/20). Instead, Clipper will dip in and out of that zone of radiation to zip past Europa at least 49 times — aiming all nine of its instruments at the moon at once — each time retreating to calmer territory to process the data and send it back to Earth.



One of the first things Clipper will do when it arrives is confirm — or possibly refute — the presence of the subsurface ocean. How the moon gravitationally tugs on the spacecraft will reveal details of its interior immediately, said deputy project scientist Bonnie Buratti of JPL in the news conference.


Next will come the pictures. Galileo’s antenna never deployed properly, so its images were not as sharp as they could have been, Phillips says. Galileo’s spectrometer wasn’t designed to work at Europa either, so scientists struggled to tease out the composition of anything that wasn’t ice on the surface. Clipper’s images and spectra will reveal clues about the chemical components of the surface and possibly the subsurface that Galileo never could.

Finally, Clipper will delve into details like the thickness of the crust, the depth of the ocean and how they interact.

There are some limitations. Clipper’s gaze won’t reach the bottom of the ocean, where rock and water meet. That might be the most likely place for microbial ecosystems to nestle themselves, similar to seafloor vents on Earth. But Clipper won’t be able to sense them directly.

There is, however, strong circumstantial evidence that water sometimes comes to the surface, whether in plumes of vapor or slower seeping streams or lakes, and may deposit any other material it’s carried up onto the ice (SN: 5/14/18). Clipper will search for chemicals on the surface and infer what could be brewing in the murky depths.

“The holy grail would be if we saw something like an amino acid on the surface,” Buratti says. “But just seeing a lot of organic molecules there will be good evidence that we have all the requisites for life.”

What Clipper won’t do is look directly for life. “We don’t have a tricorder we can point at Europa and say, ‘It’s life, Jim!’” like in Star Trek, Phillips says. “It’s going to be multiple lines of indirect evidence, again.”

“To do a life-detection mission,” she says, “you’re going to have to touch that surface.” Or maybe get beneath it (SN: 5/2/14).

With how long she’s had to wait to get to Europa, Phillips doesn’t expect to see that mission herself. But she hopes scientists won’t have to wait another 25 years.

“I hope that momentum will build,” she says. “I accept that I’m probably not going to get to see that Europa submarine, but hopefully my kids or maybe my grandkids will.”

Chemistry Nobel goes to developers of AlphaFold AI that predicts protein structures





AI tools are designing entirely new proteins that could transform medicine

For the first time — and probably not the last — a scientific breakthrough enabled by artificial intelligence (AI) has been recognized with a Nobel prize. The 2024 chemistry Nobel was awarded to John Jumper and Demis Hassabis at Google DeepMind in London, for developing a game-changing AI tool for predicting protein structures called AlphaFold, and David Baker, at the University of Washington in Seattle, for his work on computational protein design, which has been bolstered by Al in recent years.

“I hope when we look back on AlphaFold, it will be the first proof point of AI's incredible potential to accelerate scientific discovery,” Hassabis said at a press briefing at DeepMind on 9 October. “It’s so unreal at this moment.”



What’s next for AlphaFold and the AI protein-folding revolution

The impact of AlphaFold, which was unveiled just a few years ago, has been nothing short of transformative. The tool has made protein structures — often, but not always, highly accurate ones — available to researchers at the touch of a button, and enabled experiments that were unimaginable a decade ago. “It’s a major revolution,” says Christine Orengo, a computational biologist at University College London, whose laboratory has used AlphaFold-predicted structures to uncover new proteins.

“It has long been a dream to learn to predict the three-dimensional structure of proteins from knowing their amino acid sequences … for several decades, this was considered impossible,” said Nobel committee chair Heiner Linke, who researches nanoscience at Lund University in Sweden, during the prize announcement. This year’s laureates “have cracked the code”, he added. The three winners share a prize pot of 11 million Swedish kronor (US$1 million).
Award-winning AI

DeepMind debuted AlphaFold in 2018, when it won a biennial protein-structure prediction contest called the Critical Assessment of Protein Structure Prediction (CASP). But it was the second iteration of the deep-learning neural network, revealed in late 2020, that really shook up the life sciences. Many of AlphaFold2’s predictions at CASP were so accurate as to be indistinguishable from experimentally solved protein structures.

Hassabis, DeepMind’s co-founder and chief executive, and Jumper, head of the AlphaFold team, led the development of AlphaFold2. To predict protein structures, the neural network incorporates data from libraries of hundreds of thousands of structures and millions of sequences from related proteins — which hold information about their shapes.



than 200,000 protein structures determined using methods including X-ray crystollagraphy and cryo-electron microscopy. “It’s humbling every time we train [AlphaFold] on years of effort. Each data point is years of effort from someone,” Jumper said at the DeepMind press briefing.

In 2021, DeepMind made AlphaFold2’s underlying code freely available, along with the data needed to train the model. An AlphaFold database, created with the European Molecular Biology Laboratory’s European Bioinformatics Institute in Hinxton, UK, now holds the structures of almost all the proteins from every organism represented in genetic databases, some 214 million predictions in total. This year, the company unveiled a third version of AlphaFold, which can model other molecules that interact with proteins such as drugs.

The revolution that Jumper, Hassabis and their colleagues unleashed is still in its early days, and AlphaFold’s full impact on science might not be known for years. Already, the tool is helping scientists make new insights.

One pioneering team used the tool, along with experimental data, to map the nuclear pore complex, one of our cells’ largest machines that transports molecules into and out of the nucleus. Last year, two teams mined the entire AlphaFold database to uncover the darkest corners of the protein universe, identifying new families of proteins and folds and surprising connections in the machinery of life.



‘The entire protein universe’: AI predicts shape of nearly every known protein

Many researchers hope that AlphaFold and other AI tools it has inspired will transform medicine, but it is not yet clear how, or indeed whether, AlphaFold will streamline the costly and multi-step process of developing safe drugs. Scientists laying the groundwork for new vaccines are finding AlphaFold incredibly useful and, in some cases, game changing. But AlphaFold is a complement to experimental studies and other approaches to mapping and tweaking the structure of viral proteins for use in vaccines.

For most researchers, a predicted structure is the beginning of a study, not the end, says Jan Kosinski, a structural modeller at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany. “At the beginning, there was this fear that it will replace structural biology, people will lose jobs and so on. Actually, the complete opposite has happened,” he adds.

David Jones, a bioinformatician at University College London who collaborated with DeepMind on the first version of AlphaFold starting in 2016, says one of the tool’s biggest impacts has been a change in biologist’s mindset, “to say that computers are things that can produce useful hypotheses that can be tested in the lab”.
Creating new proteins

More than two decades before DeepMind started working on AlphaFold, computational biophysicist David Baker and his colleagues developed a software tool called Rosetta that modelled protein structures using physical principles. The tool compares small fragments of multiple existing protein structures and sequences to identify a protein sequence that can fold into a particular shape.

Initially, Rosetta was applied to predicting protein structures — it has been among the top entries at numerous CASPs, prior to AlphaFold’s dominance. But Baker soon realised that the model could be flipped around to design entirely new proteins.



The tool had early success designing novel proteins, including new kinds of enzymes, proteins that can bind tightly to other molecules and self-assembling protein nanoparticles that resemble viruses (one of these served as a basis for an approved COVID-19 vaccine).

When AlphaFold2 was announced — but not yet released — Baker and his team, including computational chemist Minkyung Baek, now at Seoul National University in South Korea, set out to understand the software and apply some of its tricks to a previous AI-based version of Rosetta. The first version of the resulting RoseTTAFold network performed nearly as well as AlphaFold2. Since 2021, both networks have been continually improved by their developers and other scientists to tackle fresh challenges, such as predicting the structure of complexes of multiple different interacting proteins.

In recent years, Baker’s team have been especially prolific in applying machine learning to his lab’s raison d’etre: creating new proteins never seen before in nature. A tool recently developed by Baker’s team that combines RoseTTAFold with image-generating diffusion neural networks has led to a step-change in researchers’ capacity to design proteins.
Rapid progress

Such tools have been a massive accelerator and democratizer, says Sergey Ovchinnikov, an evolutionary biologist at the Massachusetts Institute of Technology in Cambridge, who did his PhD in Baker’s lab. It used to take Rosetta weeks of running on hundreds of processors to come up with a protein design, a task that newer AI-based tools can accomplish in seconds. “Now everybody in the world can do protein design,” he says.

“I have been really deeply inspired by the others in the field and the people I’ve worked with,” said Baker, speaking by telephone at the Nobel prize announcement. “I stood on the shoulders of giants.”



Martin Steinegger, a computational biologist at Seoul National University in South Korea, likens the impact of AlphaFold, RoseTTAFold and other biological AI tools to that of the Apollo Moon missions by showing what engineering can achieve. “This is a similar moment for structure prediction and the structural biology field — just seeing what is possible,” he says.

Few were surprised with the Nobel committee’s decision. For Baker, “most people thought that it was 'a when not if’ situation, the amount of work he’s done in that field,” says Jones. Jumper, aware that he and Hassabis were on many people’s short lists, said in the press briefing that he was unable to sleep the night before today’s announement.

For Jumper, the predicted structures that AlphaFold delivers create new opportunities for scientific discovery. Millions of scientists have already used the tools, and he hopes it won’t be long before one of them gets a call from Sweden. “The moment that I will be almost as excited as this will be the Nobel Prize that talks about the work done with AlphaFold,” he said.