Restricting sugar consumption in utero and in early childhood significantly reduces risk of midlife chronic disease


A low-sugar diet in utero and in the first two years of life can meaningfully reduce the risk of chronic diseases in adulthood, a new study has found, providing compelling new evidence of the lifelong health effects of early-life sugar consumption.


Published in Science, the study finds that children who experienced sugar restrictions during their first 1,000 days after conception had up to 35% lower risk of developing Type 2 diabetes and as much as 20% less risk of hypertension as adults. Low sugar intake by the mother prior to birth was enough to lower risks, but continued sugar restriction after birth increased the benefits.


Taking advantage of an unintended "natural experiment" from World War II, researchers at the USC Dornsife College of Letters, Arts and Sciences, McGill University in Montreal, and the University of California, Berkeley, examined how sugar rationing during the war influenced long-term health outcomes.

The United Kingdom introduced limits on sugar distribution in 1942 as part of its wartime food rationing program. Rationing ended in September 1953.

The researchers used contemporary data from the U.K. Biobank, a database of medical histories and genetic, lifestyle and other disease risk factors, to study the effect of those early-life sugar restrictions on health outcomes of adults conceived in the U.K. just before and after the end of wartime sugar rationing."Studying the long-term effects of added sugar on health is challenging," says study corresponding author Tadeja Gracner, senior economist at the USC Dornsife Center for Economic and Social Research. "It is hard to find situations where people are randomly exposed to different nutritional environments early in life and follow them for 50 to 60 years. The end of rationing provided us with a novel natural experiment to overcome these problems."

Sugar intake during rationing was about 8 teaspoons (40 grams) per day on average. When rationing ended, sugar and sweets consumption skyrocketed to about 16 teaspoons (80 grams) per day.

Notably, rationing did not involve extreme food deprivation overall. Diets generally appeared to have been, in fact, within today's guidelines set by the U.S. Department of Agriculture and the World Health Organization, which recommend no added sugars for children under two and not more than 12 teaspoons (50g) of added sugar daily for adults.


The immediate and large increase in sugar consumption but no other foods after rationing ended created an interesting natural experiment: Individuals were exposed to varying levels of sugar intake early in life, depending on whether they were conceived or born before or after September 1953. Those conceived or born just before the end of rationing experienced sugar-scarce conditions compared to those born just after who were born into a more sugar-rich environment.


The researchers then identified those born around this time in the U.K. Biobank data collected over 50 years later. Using a very tight birth window around the end of sugar rationing allowed the authors to compare midlife health outcomes of otherwise similar birth cohorts.

While living through the period of sugar restriction during the first 1,000 days of life substantially lowered the risk of developing diabetes and hypertension, for those who were later diagnosed with either of those conditions, onset of disease was delayed by four years and two years, respectively.

Notably, exposure to sugar restrictions in utero alone was enough to lower risks, but disease protection increased postnatally once solids were likely introduced.

The magnitude of this effect is meaningful as it can save costs, extend life expectancy and, perhaps more importantly, quality of life, say the researchers.


In the United States, people with diabetes incur annual medical expenditures of about $12,000 on average. Further, earlier diagnosis of diabetes means significantly shorter life expectancy, with every decade earlier that a diagnosis of diabetes is made cutting three to four years off of life expectancy.

These numbers underscore the value of early interventions that could delay or prevent this disease, the researchers note.

Experts' concerns about children's long-term health as they consume excessive amounts of added sugars during their early life, a critical period of development, continue to mount. Adjusting child sugar consumption, however, is not easy -- added sugar is everywhere, even in baby and toddler foods, and children are bombarded with TV ads forsugary snacks, say the researchers.

"Parents need information about what works, and this study provides some of the first causal evidence that reducing added sugar early in life is a powerful step towards improving children's health over their lifetimes," says study co-author Claire Boone of McGill University and the University of Chicago.


Co-author Paul Gertler of UC Berkeley and the National Bureau of Economics Research adds: "Sugar early in life is the new tobacco, and we should treat it as such by holding food companies accountable to reformulate baby foods with healthier options and regulate the marketing and tax sugary foods targeted at kids."

This study is the first of a larger research effort exploring how early-life sugar restrictions affected a broader set of economic and health outcomes in later adulthood, including education, wealth, and chronic inflammation, cognitive function and dementia.

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."