A man walks past tents in the shadow of downtown L.A. skyscrapers.
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Frederic J. Brown
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AFP via Getty Images
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Topline:
Los Angeles County’s unhoused population declined slightly for the second year in a row, according to authorities responsible for the region’s annual point-in-time homeless count.
Why now: Results of the 2025 event, released Monday, show homelessness dropped by 3.4% in the city of L.A. and by 4% countywide in 2025, according to the Los Angeles Homeless Services Authority, or LAHSA. This includes the number of people in shelters and those sleeping outdoors.
Why it matters: LAHSA said several factors contributed to the reductions, including the clearing of encampments throughout the region, and nearly 28,000 people being placed into permanent housing last year – a record high.
The backstory: Last year, LAHSA reported smaller declines over the previous year in both the city and county – 2.2% and less than 1% (.27%) respectively. Prior to that, the numbers had been trending upward since 2018.
Read on ... for more on the results of the count.
Los Angeles County’s unhoused population declined slightly for the second year in a row, according to authorities responsible for the region’s annual point-in-time homeless count.
Results of the 2025 event, released Monday, show homelessness dropped by 3.4% in the city of L.A. and by 4% countywide, according to the Los Angeles Homeless Services Authority, or LAHSA. That includes the number of people in shelters and those sleeping outdoors.
Last year, LAHSA reported smaller declines over the previous year in both the city and county — 2.2% and less than 1% (.27%), respectively.
Prior to that, the numbers had been trending upward since 2018.
LAHSA said several factors contributed to the reductions, including the clearing of encampments throughout the region, and nearly 28,000 people being placed into permanent housing last year — a record high.
Mayor Karen Bass speaks at a press conference before LAHSA's annual homeless count at El Rio Community School on Feb. 18, 2025 in Los Angeles.
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Carlin Stiehl
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LAist
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“These results aren’t just data points — they represent thousands of human beings who are now inside, and neighborhoods that are beginning to heal,” L.A. Mayor Karen Bass said in a statement. “This Point in Time Count makes one thing clear: change is possible when we refuse to accept encampments as normal and refuse to leave people behind.”
Va Lecia Adams Kellum, CEO of LAHSA, said during a news conference Monday that the lower numbers of unsheltered unhoused people are a direct result of the city and county’s work with clearing encampments.
“ Over the last two years, our leaders came together to bring people inside, and their efforts have paid off,” she said.
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Homelessness in LA region dropped for the second time in two years, according to annual count
" We've made real progress toward ending homelessness, and we cannot let that momentum falter now," she continued. "The dear people on our streets are relying on us, and we must continue to focus on bringing them inside."
Elected officials react
Most city and county officials are cautiously optimistic about L.A.’s homeless count data, but they say the numbers of people experiencing homelessness are unacceptably high.
“Nobody should see these results and think our job is done,” said L.A. City Councilmember Katy Yaroslavsky. “We’re still in a crisis, but for the first time in a long time, we’re seeing the tide start to turn. We’ve learned a lot over the past few years about what it takes to resolve encampments and get people housed for good."
“This proves that when we focus resources on the things that work, we get results,” she continued. “Now we need to double down and do it faster.”
L.A. County Supervisor Lindsey Horvath said the region needs to make more investments toward solving the crisis.
"At this pace, it would take three centuries to end homelessness in Los Angeles County,” she told LAist in a statement.
L.A. City Council members noted there were some doubts about the accuracy of the data. A recent report by the RAND Corporation suggested LAHSA had systemically undercounted homelessness in some parts of the city during last year’s count in January 2024. Last month, LAist reported that LAHSA removed more volunteer observations when reconciling data in 2024 than they had in previous years.
L.A. Councilmember John Lee, who represents the Northwest San Fernando Valley, told LAist there are questions about how the homeless count numbers are validated and ultimately reported.
“When there’s this much at stake, accuracy matters and we can’t afford to make decisions based on data that may not reflect what’s actually happening on the ground,” he said in a statement. “Until we have a more reliable and consistent system of reporting, it’s difficult to fully trust that the numbers we’re seeing are telling the whole story.”
LAHSA and city leaders say the data may not always reflect the reality of every block or every street, but it remains a useful estimate of homelessness throughout the region. And that estimate is trending downward.
L.A. Council President Marqueece Harris-Dawson said the city’s efforts are working.
“I find it interesting that the folks who question the numbers this year did not have the same energy when the numbers were trending upwards, no one interrogated that data,” Harris-Dawson said in a statement. “Detractors root for failure.”
Councilmember Nithya Raman, chair of the city’s Housing and Homelessness Committee, told LAist the results reflect the reality she’s seen experienced in her district, which includes parts of Silver Lake and the San Fernando Valley.
“ The reality is that the count — if it is imperfect — is imperfect in the same way each year, and it is really meant to be a tracker of our progress over time,” Raman said.
She continued: “I'm really encouraged by the progress that we're making after years of increases, sometimes double digit increases.”
Los Angeles Mayor Karen Bass at a news conference from the Los Angeles Homeless Services Authority’s Welcome Navigation Center.
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Vitus Larrieu
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LAist
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Reaction from nonprofit leaders
Officials within the organizations that support unhoused Angelenos were pleased with the numbers but acknowledged the challenges ahead, particularly the loss of federal money that pays for housing vouchers and other services.
Peter Laugharn, president of the nonprofit Conrad N. Hilton Foundation, said systemic problems are still forcing people onto the streets.
“ Unaffordable housing is still a leading cause of first-time homelessness, and decades of economic and racial inequities continue to shape who is the most vulnerable,” he said.
Katie Hill, CEO of Union Station Homeless Services, said was concerned that the end of COVID-era federal programs, like emergency housing vouchers, would make her organization’s work more difficult.
“ The resources that made [the decline in homelessness] possible are drying up or being reduced and, in the next couple of years, we will see it's not going to be the same trend,” she told LAist. “ We need to prepare ourselves as a region, as a community to have to pick up the pieces and expect that there will be more homelessness.”
Stephanie Klasky-Gamer, president of LA Family Housing, agreed.
“ Without that type of investment, as we saw in ‘25 and in ‘24, I fear that we're going to shift from this positive trend in the years ahead,” she told LAist.
More on the results
In February, LAHSA and its volunteers counted more than 43,500 unhoused people in the city of L.A. and more than 72,000 in the county during this year’s annual tally. Those totals include people in shelters and on the streets.
The vast majority of unhoused people in the city of L.A. are living on the street rather than in homeless shelters.
For the second year in a row, that population decreased substantially. It fell by 7.9% this year, LAHSA said, and by 17.5% over the past two years. (There were 26,972 unsheltered people living in the city in February, down from 32,680 two years ago.)
Meanwhile, the number of people in the city of L.A. living in “interim housing,” or shelter, increased 4.7%. This year, LAHSA counted 16,727 people in the city of L.A. living in shelters, motel rooms and tiny homes. That’s up from 15,977 last year.
This year, the count showed fewer people living in tents and other makeshift shelters in the city of L.A. There were 13.5% fewer vehicles and tents used as shelter compared to the previous year.
The agency credits efforts like the city’s Inside Safe and county’s Pathway Home programs for moving people off of the streets. Both programs clear encampments and offer people temporary shelter with a path to possible permanent housing.
More permanent housing became available last year, LAHSA said. There were about 2,960 new apartments provided in 2024. But that was far short of an estimated 485,000 affordable homes needed.
Why the count is important
The U.S. Department of Housing and Urban Development, or HUD, requires local governments to conduct a full census of the region’s unhoused population every other year.
L.A. County has been doing a count annually since 2015, except in 2021 when it was canceled because of the COVID-19 pandemic.
LAHSA’s annual count is the largest of its kind in the country and involves coordinating thousands of volunteers who go out in groups over three nights to tally people and dwellings in more than 3,000 census subtracts.
The annual point-in-time count is typically held in late January, but this year’s count was postponed a month because of the wildfires, which were still burning in the Palisades and Altadena at the time.
LAHSA officials said they made that decision to avoid jeopardizing the safety of volunteers or the accuracy of the count, as many people were displaced from their homes or normal routines. Several wildfire-impacted areas were counted by special teams of LAHSA employees, rather than volunteers.
The delay helped depress volunteer turnout this year, LAHSA and public officials said. About 10% fewer people signed up compared with last year’s count. Some who registered this year did not show up after LAHSA moved the count back by a few weeks.
But officials at the agency said they do not believe the disaster affected the quality of the data.
This was the first year 100% of the data from the count was entered digitally, through the Esri app, and signed off by the people doing the counting, according to LAHSA. Last year, problems with the app and shifting policies for reconciling data collected through the app and data collected on paper forms led to questions about accuracy.
LAHSA representatives said the methodology for gathering the date hasn’t changed, but the tools have. Authorities said the agency is committed to producing the most accurate homeless count possible.
For the first time, LAHSA released preliminary raw data for this year’s homeless count in March, much earlier than in previous counts. The move came a week before the L.A. County Board of Supervisors was scheduled to vote on whether to pull funding from the regional agency.
LAHSA spokesperson Paul Rubenstein told the agency’s commissioners in April that it was important for stakeholders to have the early data “as they were considering significant shifts to the system.”
“Last year was not a statistical anomaly,” Rubenstein said. “The path we were on was getting us where we wanted to go.”
Adams Kellum celebrated the early results at the time.
“When I first came to LAHSA, I publicly stated that we wanted to reduce unsheltered homelessness within three years.
“We’ve done it in two.”
Criticism of LAHSA
Federal Judge David O. Carter, who is currently overseeing a major legal settlement on homelessness, said he saw the release of unverified numbers from the count as “political gamesmanship.”
“My view is that they're in a political battle for their lives right now,” Carter said.
Times have been tough for LAHSA in recent years. The agency faced fierce criticism after a county audit last year and a March report commissioned by Carter, both of which found the agency had failed to properly track spending and hold vendors accountable.
Those findings prompted the L.A. County Board of Supervisors to vote in April to shift hundreds of millions in taxpayer funding for homeless services away from LAHSA and create a new county homelessness department to eventually administer the funds itself.
The city is weighing a similar move.
Days after the county pulled out of LAHSA, Adams Kellum announced her resignation as CEO. Adams Kellum, a Bass ally, has led the organization since 2023.
Even though LAHSA’s role is being reduced, the agency remains tasked with overseeing the annual homeless count. However, Adams Kellum told the agency’s commissioners last month LAHSA may not have enough funding to do a proper count next year, because of city of L.A. budget cuts and the recent county funding decision.
“We anticipate that the current allocations will not provide enough funding for LAHSA to conduct an unsheltered count in 2026,” she said.
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.
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Nathan Solis
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The LA Local
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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.
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.”
Josie Huang
is a reporter and Weekend Edition host who spotlights the people and places at the heart of our region.
Published September 5, 2026 5:00 AM
A MINISO logo is displayed on a sign outside of a store in San Diego.
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Kevin Carter
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Getty Images
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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’sHot 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 tonearly 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 99 Ranch market opened in 2023 in Eastvale.
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Gina Ferazzi
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Los Angeles Times via Getty Images
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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.
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Fiona Ng
is LAist's deputy managing editor and leads a team of reporters who explore food, culture, history, events and more.
Published September 5, 2026 5:00 AM
Hong Pham, aka That Peking Duck Guy, takes a roasted Pipa duck out of his outdoor oven.
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Fiona Ng
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LAist
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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 behindThat 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 itPeking 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.
Peking duck from That Peking Duck Guy served with Chinese sweet sauce, chopped spring onions and cucumber slices.
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Fiona Ng
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LAist
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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
Pham and one of his special outdoor ovens he uses to roast duck.
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Fiona Ng
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LAist
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He researched how to get that extra crisp online and landed on an oven people in Asia use to make roast and Peking ducks.
"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 Pipa ducks inside the oven.
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Fiona Ng
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LAist
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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:
He usually trims off the legs and the wings, because those parts get burnt in the oven.
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.
He scalds the skin with a combination of vinegar and maltose to make it "aerodynamic and tight" to get that crispiness.
He seasons the inside of the duck.
He then hangs and dries the ducks for about 7 to 10 days.
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.
Courtesy of the UCSF Quantitative Biosciences Institute
)
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.