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The most important stories for you to know today
  • What kids learn in transitional kindergarten
     Five small children laugh as they chase each other around a jungle gym, painted in primary colors.
    Students from Downey Unified's Price Elementary take a break from the classroom.

    Topline:

    Every 4-year-old in California can now go to school for free in their local districts. The new grade is called transitional kindergarten — or TK — and it's part of the state’s effort to expand universal preschool.

    What is transitional kindergarten? For many students, transitional kindergarten is their first introduction to a formal school preschool setting.

    How did transitional kindergarten become a thing? In 2021, Gov. Gavin Newsom and the state legislature moved forward a $2.7 billion plan so that all 4-year-olds could attend by the 2025-26 school year. While it’s not mandatory for students to attend, districts must offer them as an alternative to private preschool.

    Why it matters: As a free option, it can save parents a lot of money. But it also has to be weighed against the advantages parents might have by sticking with their current childcare/pre-K option.

    Read more to understand what TK looks like in different schools across Southern California.

    Listen 4:01
    California schools now offer a free preschool option. Here's what kids really learn in it

    Every 4-year-old in California can now go to school for free in their local districts. The new grade is called transitional kindergarten — or TK — and it's part of the state’s effort to expand universal preschool.

    In 2021, Gov. Gavin Newsom and the state legislature moved to expand transitional kindergarten in a $2.7 billion plan so that all 4-year-olds could attend by the 2025-26 school year. (Prior to this, TK was only available for kids who missed the kindergarten age cutoff by a few months). While it’s not mandatory for students to attend, districts must offer them as an alternative to private preschool.

    As a free option, it can save parents a lot of money. Parents also must weigh how sending their kids into a school-based environment compares to a preschool they might already know and like, as well as other needs like all-day care, and how much play their child does.

    One big question we’ve heard: What do kids actually do and learn in a TK classroom? Educators say it’s intended to emphasize play, but what does that mean?

     A student with dark skin tone and brown hair in braids with pink beads spins in a chair-like toy on the playground.
    A social skill students can learn in transitional kindergarten is how to take turns on the playground.
    (
    Mariana Dale
    /
    LAist
    )

    To help parents get a better sense of this new grade as they make their decisions, LAist reporters spent the day in three different classrooms across the Southland. Here are five things we saw children do.

    Get used to the structure and routines of school

    For many students, transitional kindergarten is their first introduction to a formal school preschool setting. Crystal Ramirez sent her 4-year-old to TK at Marguerita Elementary School in Alhambra, so he could get used to the rhythm and rigors of school.

    “I didn't wanna put him straight into kindergarten when he was five, six, so he at least knows a routine, already,” she said. “Now, as soon as he sees that we’re in school, he loves it.”

    TK students, like other elementary school students, follow a schedule: morning bell, recess, lunch, second recess and dismissal. They’re also learning how to listen to instructions or stand in a line. Some are learning to go to the cafeteria for lunch.

    Imperfect Paradise Main Tile
    Listen 31:40
    All 4-year-olds in the state of California now have access to a free preschool program in their local school district. In this episode of Imperfect Paradise, we break it down with the LAist education team.
    California's new public preschool program for 4-year-olds: Exploring transitional kindergarten
    All 4-year-olds in the state of California now have access to a free preschool program in their local school district. In this episode of Imperfect Paradise, we break it down with the LAist education team.

    “ I wanna make sure that their first experience in a public school setting is one that is joyful, where they feel loved, where they feel welcomed, where they get to really transition nicely into like the rigor of the school,” said Lauren Bush, a TK teacher at Lucille Smith Elementary in Lawndale.

    Claudia Ralston, a TK teacher at Marguerita Elementary, said it can be hard for young kids to get up early and leave their moms and dads. But seven weeks in, many of her students have learned their routines already. She helps with the morning transitions by turning on soft instrumental music in the classroom, and allowing them free play until they regroup on the mat to discuss the day.

    “They're four years old. I want them to feel safe at school, know that this is a special place for learning and that they play,” she said.

    Learn how to socialize and communicate

    In TK, social-emotional learning is a big part of the curriculum. That’s a fancy word, but it just means they’re learning how to be in touch with their emotions

    At Price Elementary in Downey, the teacher has her kids give an affirmation: "I am safe. I am kind. I matter. I make good choices. I can do hard things. All of my problems have solutions!" (They also have these sentences on classroom wall signs.)

    The children also learn how to interact with their peers. In some schools, there are no assigned desks so the kids can learn how to share the space.

    “ They're able to problem solve. They're able to use communication to get their needs, regulating their emotions. They do better than students who come in without this experience,” said Cristal Moore, principal at Lucille Smith Elementary.

    On the playground, a student named Ava told teacher assistant Lizbeth Orozco that another student pushed her.

    “How did that make you feel?” Orozco asked.

    “Mad!”

    Orozco encouraged Ava to express her feelings to her classmate.

    “ We give them options of how to solve a problem and then they go in and solve it themselves,” Orozco said. “If they need extra help, they always come back and we can help them.”

    Arguing over toys can be a common occurrence in a TK classroom. At Price Elementary in Downey, educators help kids work through a solution. On a recent morning, one 4-year-old used two tongs to pick up paper shapes in a sensory bin, leaving another kid upset.

    “What’s the rule about sharing?” asked Alexandria Pellegrino, a teacher who gives extra support for one TK classroom.

    The boy handed over a tong to his peer. “Thank you so much for being a good friend,” Pellegrino said.

    A woman in a black shirt and medium-tone skin pinky shakes a boy wearing a large gray backpack. A door shows different cartoon images of greetings like a hug, wave and fist pump.
    Teacher Claudia Ralston greets a student at the start of school at Marguerita Elementary School in Alhambra.
    (
    Elly Yu
    /
    LAist
    )

    “[It’s]  about being kind friends and making friends and using our manners. So we do build that foundation at the beginning of the year,” said Samantha Elliot, the classroom’s lead instructor.

    At the end of the day in Alvarez’s Lawndale TK class, she counts up the stars next to each student’s name earned throughout the day — earned for positive behavior like being kind, solving problems, trying something challenging, or showing effort in other ways. Ten stars earns a small prize from the treasure chest.

    “If we don’t get something today are we going to get mad?” Alvarez asked the class.

    “No!” they responded.

    “I’m not going to cry!” one boy piped up, followed by his classmate and a “Me too!” from another student.

    “That’s [a] positive attitude,” Alvarez said. “Because tomorrow you can get more stars!”

    Get exposed to numbers, shapes, letters

    In Elliot’s TK class, students use their own little lightsabers to trace letters in the air.

    “They're learning the letter, the sound, and then a little action to go with it. They're wiggling and moving and they're also learning those letter sounds and they don't really realize, so it's incorporating instruction,” she said.

    A student with light skin tone and brown hair traces a lower-case letter a in red paint with a q-tip. The paper he is painting has Mateo printed in black.
    Students in Lauren Bush's TK class practice tracing their names in paint.
    (
    Mariana Dale
    /
    LAist
    )

    There’s no mandated curriculum in TK, but instruction is supposed to align with the state’s Preschool/Transitional Kindergarten Learning Foundations. “Kindergarten is basically where the state standards go and kick in. There are standards in TK, but it's a little bit different,” said Tom Kohout, principal at Marguerita Elementary.

    Students might put playdough into letter molds, or the teacher might pull out toys from a bag that all start with a letter “E.” Kids will play with little plastic toys that connect — or “manipulatives” — that can help them recognize numbers and patterns.

    “It’s play with a purpose,” Ralston said. “They're just being introduced to the numbers, the colors, writing. But again, we're not doing worksheets.”

    Build fine motor skills

    Molding pretend cakes with kinetic sand. Connecting small LEGO bricks. Cutting playdough. It might not seem like much, but children this age are still learning how to use their bodies.

    “Tearing paper is really hard and it's a really amazing fine motor skill for them because the same muscles you use to tear paper are the same muscles that you use to hold a pen or a pencil,” said Lauren Bush, a TK teacher at Lucille Smith Elementary in Lawndale.

    “You see kids playing with dinosaurs. I see kids sorting by color, doing visual, you know, eye hand coordination and visual discrimination. I see them using their fine motor skills,” she said.

    At lunch, kids learn how to open up a milk carton or open a packaged muffin. At PE, they learn to balance on a block or walk in a straight line — learning spatial awareness.

    “They’re learning how to run, stop, things like that and playing because their bodies are so young,” said Principal Kohout.

    Learn independence

    For some kids, it might be the first time where mom and dad aren't there to help carry their backpacks or help them go to the bathroom. TK is meant to help focus on their independence, though aides can help.

    TK classrooms are also usually set up with play centers, so kids can have the choice to explore on their own.

    “ I want them to be independent, to be able to solve their problems, you know, with assistance,” Ralston said.

    Samantha Elliot, the TK teacher in Downey, says she encourages kids to talk to their teammates first to figure out an activity before going to a teacher.

    “It's just gaining the confidence and building that independence from basically the start of the school year,” she said.

    Parent Crystal Ramirez has already noticed a change in her 4-year-old this year since starting school. “ [He’s] socializing a little bit more, talking a little bit more, trying to express himself as well.”

    Share your experience

  • Unhoused man died after entering interim housing
    Exterior of the Mayfair hotel in Koreatown
    Raz Chowdhury, a 45-year-old unhoused man, died at The Mayfair in July 2026 after being moved to hotel as part of the Inside Safe program.

    Topline:

    45-year-old Raz Chowdhury was moved off the streets into interim housing through an Inside Safe operation. A week later, he was found dead in his hotel room.


    The backstory: L.A. Mayor Karen Bass’ office said it does not disclose the locations where an individual is placed following an Inside Safe operation. According to Ktown for All, Chowdhury died at the Mayfair Hotel in Westlake, which is used for interim housing.

    A spokesperson for the Los Angeles County Department of Medical Examiner said the case is still under investigation and Chowdhury died at a hotel in the 1200 block of West 7th Street.

    This story first appeared on The LA Local.

    A week after 45-year-old Raz Chowdhury was moved off the streets into interim housing through an Inside Safe operation, he was found dead in his hotel room.

    Chowdhury had spent years living on the streets of Koreatown, moving between encampments along Sixth Street and Wilshire Boulevard and Manhattan Place.

    Sherin Varghese first met him three or four years ago. Chowdhury would reach out to Varghese, a volunteer with Ktown for All, an advocacy group that provides direct aid for people experiencing homelessness in Koreatown. He would ask her for tents, tarps, clothes and other supplies. More often than not, she said, they weren’t for him.

    “He would always go above and beyond to take care of the people around him,” Varghese said at a vigil for Chowdhury on Saturday, Aug. 29.

    Once, after Chowdhury lost his phone during a sanitation sweep, he searched for Varghese online and found her work number. He called to ask if she could bring tents and tarps for him and other people whose belongings were lost in the sweep.

    “He was resourceful, he was reliable, and he was so thoughtful about the way that he talked about how all of this affected him and affected his friends,” Varghese said.

    On June 25, Chowdhury was among 31 people moved into housing during an Inside Safe operation at Wilshire Boulevard and Manhattan Place, according to Mayor Karen Bass’ office.

    A week later he was dead.

    What happened after Inside Safe

    According to Ktown for All, Chowdhury died at the Mayfair Hotel in Westlake, which is used for interim housing.

    A spokesperson for the Los Angeles County Department of Medical Examiner said the case is still under investigation and Chowdhury died at a hotel in the 1200 block of West 7th Street on July 2. His cause of death is listed as deferred and the case is under investigation by the Los Angeles Police Department’s Rampart Division.

    The Los Angeles Homeless Services Authority, which oversees the Mayfair, would not say if Chowdhury was a resident when he died. An agency spokesperson said they cannot confirm an individual’s enrollment in a LAHSA-contracted program without a written release from next of kin.

    LAHSA’s latest Inside Safe report shows that 6,406 people had entered interim housing through the program as of July 31. About 1,750 people remained in interim housing, including 289 at the Mayfair. Meanwhile, 1,802 people, or more than one in four who entered the program, had returned to homelessness. Another 126 people, or about 2%, were listed as deceased.

    Bass’ office said it does not disclose the locations where an individual is placed following an Inside Safe operation.

    Once someone is connected to interim housing, ongoing services and case management are handled by a LAHSA-contracted service provider, mayor spokesperson Jieun Kim said.

    Remembering Chowdhury

    The people who knew Chowdhury gathered last week to remember him at the site of the encampment where he had lived at Wilshire Boulevard and Manhattan Place.

    A little more than two dozen people attended the memorial, where they placed flowers at the base of a small tribute to him.

    Planters now line the sidewalk where the tents once were. Several people cried as they shared memories of Chowdhury, who they said spent years looking out for others living on the streets of Koreatown.

    Cynthia Zhang, who has volunteered with Ktown for All for about four to five years, remembers visiting an encampment where Chowdhury was staying after the Los Angeles fires. Newly displaced people there told her they felt safer with that community than they did at shelters.

    “I think Raz was really instrumental in helping create that kind of space,” Zhang said at the vigil.

    The last time Zhang saw Chowdhury, he had moved again and did not have a lot of his stuff. But he had a new puppy named T-Rex and seemed to be in good spirits.

    “He had a really lovely smile,” Zhang said. “I just remember him skateboarding around … all these little things, maybe because I didn’t see him every day, it really does feel like I’ll be walking around and I’ll see him in one of our old spots.”

    David Strugar, another longtime Ktown for All volunteer, said Chowdhury was often the person volunteers went to when they wanted to know how people in the area were doing.

    “I would always point him out and say, ‘That’s the mayor of this area,’ because wherever he was, he was just the center of it, and he took care of people,” Strugar said.

    Chowdhury would tell volunteers who needed what and help distribute supplies, Strugar said.

    A few weeks before he died, Varghese said, she and Chowdhury were looking for places where he could stay outside a 41.18 zone, where the city restricts sitting, lying, sleeping and storing personal property in certain public rights-of-way under specified circumstances.

    Then Inside Safe moved him indoors.

    “I hoped that he’d be one of its success stories, but a week later, he was gone,” Varghese said. “The program is called Inside Safe, but for Raz and 125 others, it wasn’t that. And it was never going to be Inside Safe, and it was never going to be easy to be inside alone for someone who had so much to give and always surrounded himself with people to take care of.”

    The last time Strugar saw Chowdhury, he had his dog T-Rex with him. Ktown for All volunteers don’t know where T-Rex is now.

    Chowdhury believed he had the right to community and companionship, Strugar said.

    “And there are so many people who have so much and won’t give anything,” Strugar said. “And Raz kept having everything taken away from him, and he still ended up being the person to give.”

    He added, “I just keep expecting to walk around the corner and see him, and I’m angry that I won’t.”

  • Sponsored message
  • SoCal is a launchpad
    A sign of the company Miniso's red shopping bag logo.
    A MINISO logo is displayed on a sign outside of a store in San Diego.

    Topline:

    SoCal has become a proving ground for some of the country’s fastest-growing Asian and Asian American retailers, giving chains like Miniso and 99 Ranch Market an early test of broader U.S. appeal.

    Growing fast: On the National Retail Federation’s 2026 Hot 25 list, Miniso ranks No. 1, Daiso No. 3, Uniqlo parent Fast Retailing No. 6 and 99 Ranch Market No. 15.

    Backstory: All four have had a Southern California presence for years, giving them experience in one of the country’s most diverse and competitive retail markets.

    Southern Californians who’ve long shopped at Daiso, Miniso, Uniqlo or 99 Ranch Market may not be surprised to see the Asian-rooted chains expand across the country.

    But that growth is now showing up in the numbers.

    The National Retail Federation’s Hot 25 Retailers list ranks retailers by U.S. sales growth from 2024 to 2025. Miniso tops the list, with sales up nearly 53%.

    The Chinese chain of gift shops opened its first U.S. store in Pasadena’s Old Town more than nine years ago and is now aiming to grow its American footprint to nearly 500 stores this year.

    “If you can make it in Southern California, that's great,” said David Marcotte, senior vice president of global retail and technology at Kantar and an author of the NRF list.

    A store clerk gathers grocery carts outside a 99 Ranch supermarket
    A 99 Ranch market opened in 2023 in Eastvale.
    (
    Gina Ferazzi
    /
    Los Angeles Times via Getty Images
    )

    Marcotte says succeeding in California’s highly competitive retail market can teach chains lessons that translate elsewhere.

    “The stone-cold reason is quality. The second one is experience,” he said. “Those are the two things that when shoppers go into any retailer, they’re looking for.”

    Daiso ranks third, with growth of nearly 26%, while another Japanese company, Fast Retailing — the parent company of Uniqlo — comes in sixth.

    99 Ranch Market, an American supermarket chain founded in Orange County that specializes in Asian groceries, comes in 15th.

    Marcotte says Southern California has been a logical landing spot for these companies because of its proximity to Asia. But Marcotte says it can also be an unforgiving place to launch because of the competition, and he often encourages the clients he advises to consider smaller markets.

    “I said if you open in Southern California, open one store, get it right,” Marcotte said. “If you get it wrong, you're dead. You'll never recover. You'll have to leave the country and come back in.”

    The supermarket industry is particularly tough to break into because customers here, he says, have plenty of alternatives if the quality, selection or experience falls short.

    He also emphasizes a retailer in California focused on Asian goods will see more success serving Chinese, Filipino and other Asian customers rather than designing around a particular ethnic group.

    “That type of diversity of Asian customers that you have to address in the same store is what really proves to be the difference for an Asian retailer in the California market,” Marcotte said.

    That’s part of the business model for 99 Ranch, which was founded by a Taiwanese immigrant who opened the first location in Westminster's Little Saigon in 1984.

  • SoPas doctor makes backyard roast for fun
    An Asian man wearing glasses and an apron holds a roasted duck above a big outdoor oven.
    Hong Pham, aka That Peking Duck Guy, takes a roasted Pipa duck out of his outdoor oven.

    Topline:

    Radiologist Hong Pham has an unusual side hustle — cooking and selling Peking and roast ducks from his South Pasadena backyard.

    The backstory: That Peking Duck Guy started out as a social media account documenting Pham's culinary journey to make the perfect duck. It then became a side hustle when strangers and neighbors offered to buy his birds.

    Read on ... to learn about how Pham got started and how he cooks his ducks.

    Got a taste for ducks cooked the Chinese way? Your quest may take you to a quiet suburban backyard in South Pasadena.

    That's where That Peking Duck Guy cooks and sells his birds. His clients, he said, include Phil Rosenthal and Roy Choi.

    The guy behind That Peking Duck Guy is Hong Pham, who started the social media account in late 2025 as a way to document his latest culinary obsession: making the perfect duck, be it Peking or Pipa (deboned and flattened into the shape of the namesake Chinese string instrument).

    The intention was not to sell. "I have a day job," Pham said. A radiologist, to be precise.

    "I was actually making so many that neighbors wanted to claim it and offered to buy it," he added. "So I'm like, 'OK, that makes it easier 'cause I don't have to eat it all.'"

    Soon came DMs from strangers asking for the same thing.

    These days, That Peking Duck Guy caters events and holds takeout pop-ups where people can purchase and pick up a duck (which comes with sides and duck soup) from his South Pasadena backyard — right where he cooks them.

    A plate of duck served with Chinese sweet sauce, chopped spring onions and cucumber slices.
    Peking duck from That Peking Duck Guy served with Chinese sweet sauce, chopped spring onions and cucumber slices.
    (
    Fiona Ng
    /
    LAist
    )

    Duck is the latest obsession

    Duck is not his first rodeo. Pham said he and his wife are foodies who've always been curious about delving into Vietnamese and other Asian culinary traditions. For Pham, that also means replicating some of these dishes at home, from scratch.

    He'd gone on a tofu bender — making gallons of the stuff, as blocks, drinks and pudding — and also a bánh cuốn spree, or Vietnamese steamed rice rolls. He landed on duck as his latest subject only because he had wanted to make better heo quay, or Vietnamese roasted pork belly.

    It's the oven

    An Asian man in glasses and an apron smiling next to a spaceship-like outdoor oven.
    Pham and one of his special outdoor ovens he uses to roast duck.
    (
    Fiona Ng
    /
    LAist
    )

    He researched how to get that extra crisp online and landed on an oven people in Asia use to make roast and Peking ducks.

    How to get your duck

    Pham hosts takeout pop-ups from South Pasadena backyard. Follow That Peking Duck Guy's Instagram for updates.

    Visit the official website for catering requests.

    "It was called the Apollo oven 'cause it looks like an Apollo space capsule," he said.

    He bought one and then another. In between, he experimented cooking different meats with the new oven to get a feel before turning to the waterfowl.

    He even got advice from Top Chef winner Mei Lin, whom he messaged cold: "She's like, 'Keep it simple. Keep it basic. Keep it traditional.'"

    Three ducks inside an outdoor oven
    Three Pipa ducks inside the oven.
    (
    Fiona Ng
    /
    LAist
    )

    Hundreds of ducks later, Pham said he still learns something new. That's one reason why his side hustle has stuck around.

    "I didn't create like, you know, That Bánh Cuốn Man," he said. "Yeah, duck's gonna last."

    How That Peking Duck Guy cooks his ducks

    Pham starts 7 to 10 days before cooking. Here's the preparation process:

    1. He usually trims off the legs and the wings, because those parts get burnt in the oven.
    2. He insufflates the duck. He sticks an air pump in between the meat and the skin to separate the two, so the entire duck blows up into a "huge balloon essentially," he said.
    3. He scalds the skin with a combination of vinegar and maltose to make it "aerodynamic and tight" to get that crispiness.
    4. He seasons the inside of the duck.
    5. He then hangs and dries the ducks for about 7 to 10 days.
    6. Then in the Apollo oven they go. Peking ducks take about an hour and 15 minutes to cook. Pipa ducks take about 40 minutes.

    When does he know they're done? "Well, you know the color, we're looking for that beautiful mahogany glistening skin, you know?" Pham said.

    Two freshly cooked roast ducks.
    Two Pipa ducks fresh out of the oven.
    (
    Fiona Ng
    /
    LAist
    )

  • UC scientists map interactions in new research

    Topline:

    Scientists have now gotten closer to understanding how gene mutations may lead some people to develop profound autism.

    Why it matters: A team of researchers from UC San Francisco mapped more than a thousand interactions between many proteins that come from certain autism risk genes.

    Why now: This molecular atlas, published in the journal Science, could point researchers toward new and promising treatments.

    Scientists have now gotten closer to understanding how gene mutations may lead some people to develop profound autism.

    The clues, they say, lie in the murky space between genes and disease — where key proteins come together and interact.

    A team of researchers from UC San Francisco mapped more than a thousand interactions between many proteins that come from certain autism risk genes. This molecular atlas, published in the journal Science, could point researchers toward new and promising treatments.

    "It's an unprecedented resource for the field," says Dr. Daniel Geschwind, a professor of human genetics, neurology, and psychiatry at UCLA who was not involved with the study. "A lot of people interested in understanding autism and drug development are going to be using this."

    For families affected by profound autism, it offers hope for eventual drug therapies. "This is the kind of scientific advance we have been waiting for and praying for," says Alison Singer, president of the nonprofit Autism Science Foundation, who has a daughter with severe cognitive impairment. "There's still a lot of work ahead, [but] this paper makes the path from genetic discovery to treatment much clearer."

    The work builds on progress made in recent years to identify single genes that harbor mutations found in a subset of individuals with profound autism.

    Getting past the "wall"

    People with profound autism often live with severe intellectual disability and require around-the-clock care. They're nonverbal or minimally verbal, and often have serious medical conditions like epilepsy.

    Pinning down the biology behind profound autism has always been a complicated endeavor — while both genes and environmental factors play a role, those factors can vary widely from person to person.

    In the past decade or so, some genetics researchers have had remarkable success in identifying high-impact genetic differences in a subset of people with profound autism.

    "They've discovered several hundred genes and corresponding mutations that are prevalent in [these] individuals," says Nevan Krogan, director of the Quantitative Biosciences Institute at UC San Francisco.

    "But they kind of hit a wall," he added — because scientists haven't been able to turn those gene discoveries into many promising drugs and treatments.

    "There was this huge missing piece," says Dr. Matthew State, a clinical psychiatrist and geneticist at UCSF: The genes serve as blueprints for making proteins that drive brain development, but researchers lacked visibility into how those proteins do the work.

    State has been a pioneer in identifying high-risk genes, and the mutations in those genes, that are associated with profound autism. Krogan has been at the forefront of using new technology to look into protein interactions.

    More than a decade ago, the two researchers were introduced by their mutual boss, the chancellor at UCSF, who encouraged them to collaborate. "[State] had the genes and the mutations. I had the technologies to look at the corresponding proteins," Krogan says.

    They focused on filling a knowledge gap. "What we've been missing is the mechanistic understanding of how these mutations [on the genes] are seemingly resulting in autism," Krogan says. "In order to understand that, you need to go to the proteins."

    Proteins are the complex molecules that come together to build the body, based on instructions encoded in the genes. "What makes an eye cell an eye cell, and a muscle a muscle, are the proteins and how they work together," State says. "They are the machinery of life."

    In this case, the researchers wanted to find the molecular machinery of profound autism — to understand which proteins came from those high-risk autism genes, and how those proteins worked together.

    The research was slow at first, but more recent advances in technology — including artificial intelligence — have sped things up.

    To start, the researchers went on a "fishing expedition" for protein interactions. They chose 100 proteins from these high-risk autism genes, injected them into lab-grown cells, and then pulled them out, along with the additional proteins that attached to them.

    Then, they used an AI system called AlphaFold, developed by Google DeepMind, to help determine which proteins in the clumps were directly touching. "Where AI is playing an important role is being predictive about who's talking to who," says Krogan. "Sometimes they take years to figure out. Now, we can get these insights in an hour." While imperfect, the system has worked well enough to save significant time and money, Krogan says.

    Then, they wanted to see what happened to the proteins when the genes got tweaked. They introduced mutations that appear in patients with profound autism, and assessed what changed. "We broke the proteins in the way that they're broken in autism," says State. "That allows us ultimately to answer the question of, when they're going wrong in autism, how are they going wrong?"

    They conducted this research in frogs and in organoids, which are lab-grown tissues that model the human brain. In one example, the mutations weakened the connection between two proteins related to which genes turn on and off in a cell. Then, one went rogue, turning on other genes that led to neurodevelopmental defects in organoids.

    Molecular convergence

    There are hundreds of rare, high-risk autism genes, acting in more than a thousand different ways.

    But in mapping more than 1,800 protein interactions, the researchers found that many of them moved along shared biological pathways — particularly those related to early brain development, such as how synapses get constructed, and which neurons develop and when.

    The convergence found in this study aligns with other recent publications, adding to an emerging understanding in the field, says Dr. Geschwind of UCLA.

    "If we look at multiple mutations and they converge on the same process, that's strong evidence that you're dealing with the things that you want to treat," State says.

    Identifying this more limited set of protein complexes that likely contribute to the development of profound autism could change the approach to treatments, says Singer with the Autism Science Foundation. "We've been working gene-by-gene to correct mutations," she says.

    And if future drugs could target these shared protein pathways, she adds, "we may not need that separate therapeutic strategy for every autism gene."

    Setting sights on new drug-development targets

    It takes years to go from a biological discovery like this to an approved drug that treats humans. The findings would need to be translated into drug candidates, then tested for safety and effectiveness.

    "It takes time and a lot of persistence and focus," State says. "This [paper] is unlikely to lead to therapies tomorrow — but it lays an important foundation for them."

    Most human drugs are made to target proteins, Geschwind at UCLA says, so the newly published map of protein interactions offers an accessible entry point for pharmaceutical development.

    And researchers hope to combine recent technological advances in ways that accelerate that progress even more. "When you put together the ability to borrow from successes in other fields [such as cancer treatments], and the development of AI, we're at an inflection point that will hopefully shorten the time cycle," State says.

    Last week, Krogan's Quantitative Biosciences Institute received a $46 million grant from the Aligning Research to Impact Autism initiative, funded by philanthropist and Google co-founder Sergey Brin. The researchers are already working on next steps.

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