Four years after the U.S. went into lockdown, the worst of the pandemic has passed. But for people with long COVID, the illness remains a daily misery.

The new research suggests why: The virus is not always fully cleared after the initial infection, so remains deeply embedded, even though people are no longer contagious.

It is not yet known if these small viral proteins, called antigens, are causing long COVID. But, based on the new discovery, the UCSF team is conducting clinical trials of potential therapies that could attack the hidden pathogen.

“This can be a persistent infection for some people,” said Dr. Timothy Henrich, professor of medicine at UCSF who co-authored the research, presented at last week’s Conference on Retroviruses and Opportunistic Infections in Denver. “We’re concerned that this could be leading to, at least in part, some of the long COVID symptoms that people have been experiencing.”

While COVID remains much more serious than the usual seasonal flu, safe and highly effective vaccines have caused a dramatic decline in infections and deaths.

There is a desperate need for a diagnostic test and treatment for long COVID, which affects an estimated 7% of American adults. Currently, doctors are only treating the symptoms, rather than offering a cure. Experts predict that the disorder will place continuing demands on our healthcare system.

“Long COVID patients deserve swift, accurate diagnosis and timely, effective treatment,” said Jaime Seltzer, scientific director at the nonprofit MEAction, which advocates for patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS.

Is the clandestine virus constantly provoking the immune system, causing symptoms? That’s one leading theory. Another possibility is that COVID triggers an autoimmune response when the body mistakenly attacks itself. Or perhaps, long after it fends off infection, the immune system fails to turn off.

Using an ultra-sensitive test of blood from 171 people who had been infected with COVID, the UCSF scientists found pieces of the viral “spike” protein that persisted up to 14 months after infection.

Viral proteins were identified in 7% to 14% of the patients.

The likelihood of detecting the protein was about twice as high in people who had been severely ill, requiring hospitalization, than those who were not, according to the team. Detection was also higher in the blood of people who reported being very sick, but were not hospitalized.

In a second study involving tissue samples, traces of the virus were found up to two years after infection. It hid in connective tissue where immune cells are located. The work was conducted at UCSF’s Long COVID Tissue Bank, the world’s first tissue bank with samples donated by patients with long COVID.

Patients are not infectious because the virus is not living in the respiratory tract, where it could be spread by coughing or sneezing, said UCSF’s Henrich. Instead, “there seems to ‘seeding’ of deeper tissue after the initial infection, that may persist over a long period of time.”

The team is now designing studies to target the persistent virus. Hopes are pinned on a monoclonal antibody – a lab-made protein that effectively attacks viruses – and an antiviral therapy that blocks viral replication.

“There is a lot more work to be done, but I feel like we are making progress in really understanding the long-term consequences of this infection,” according to infectious disease expert Dr. Michael Peluso, who led the UCSF study.

This is worrisome because these persistent active infections may act as viral “reservoirs” that lead to new and highly genetically divergent lineages, seeding a future outbreak.

That study found that the risk of long Covid was 55% higher in people with persistent infection.

“We’re making considerable headway on understanding what drives long Covid,”  wrote Dr. Eric Topol, director of the Scripps Research Translational Institute in La Jolla.

“Clearly finding effective and safe treatments is an urgent matter and not enough is being done to pursue that yet, despite a long list of potential alluring interventions based on mechanistic insights,” he said. “Hopefully that will get going now — it cannot happen soon enough.”

The study, published on Thursday in the journal Science, adds to our understanding of long COVID, the lingering and often debilitating symptoms experienced by some people. One significant finding revealed shifts in proteins the body produces in response to inflammation that may persist months after infection. Another detected blood clots and tissue injury.

“We identified common patterns in long COVID patients not recovered at six months after acute infection,” compared to healthy patients, wrote the team, a collaboration of scientists from New York City’s Icahn School of Medicine at Mount Sinai, Switzerland, Sweden and London.

There is tremendous need to diagnose and find effective ways to treat long COVID, a constellation of symptoms that include exhaustion, migraines, brain fog and nausea that are not explainable using conventional lab tests.

At a hearing in Washington D.C. this week, senators at the Senate Committee on Health, Education, Labor and Pension agreed that the government must become more involved in long COVID research and support. Sen. Tim Kaine, D-Va., said he has been struggling with symptoms of long COVID for four years.

On March 15, a demonstration is planned at Lincoln Memorial to raise awareness and urge greater funding, preventative measures, research, and treatment strategies.

Although long COVID’s prevalence is difficult to estimate, surveys suggest it may afflict 5.3% to 7.5% of people infected by the virus.  It’s not known why some people develop long COVID and others don’t. But vaccines offer protection. One dose of vaccine reduces risk by 21%, two doses reduce risk by 59%, and three or more doses reduce risk by 73%, according to a recent study.

What causes long COVID? One possibility is that, long after it fends off infection, the immune system is still fighting. It turns on — but doesn’t turn off.

Experts don’t know why. UC San Francisco research suggests that viral genetic material remains embedded in tissues, long after infection. Or perhaps COVID triggers an autoimmune response when the body mistakenly attacks itself. There is mixed evidence for the effectiveness of the antiviral drug Paxlovid in preventing long COVID.

There is a desperate need for a diagnostic test and treatment for long COVID. Currently, doctors are treating the symptoms, rather than the underlying cause.

The new findings are important because “they demonstrate dysfunction, which is important to patients,” said Jaime Seltzer, scientific director at the nonprofit MEAction, which advocates for patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS.

“Secondly, they point the way to potential treatments, and even possibly mechanisms” of disease, she said.

This paper builds on our understanding of long COVID by connecting the changes that occur during an acute infection to longer-term abnormalities in markers of blood cell function, said Dr. Michael Peluso, an infectious disease physician at Zuckerberg San Francisco General Hospital, who is studying the biological mechanisms that drive long COVID and the infection’s long-term impact on health.

“It suggests that there is a relationship between the virus, its immune effects, and changes in certain blood coagulation pathways,” he said.

Although the study represents another step forward in understanding the science of long COVID, it will not immediately change the approach to diagnosing or treating the condition, said Peluso.

“We need more investment in larger studies to build upon these findings, as well as clinical trials to test whether altering some of the abnormalities that have been found here could result in symptomatic benefit,” he said.

In the new study, scientists analyzed changes in the blood of 113 patients who either fully recovered from COVID-19 or developed long COVID, as well as healthy people.

Specifically, they measured levels of 6,596 different proteins in study participants over a year, then sampled the blood again six months and a year later.  Proteins act like keys that fit in multiple locks on the surface of cells. Changes in proteins mean that cellular processes are altered.

Immune dysfunction is also suspected to be driving the symptoms in those with other persistent infection-linked illnesses, such as ME/CFS and Lyme Disease, said Seltzer. It’s the body’s way of adapting, she said.

There are caveats. With only 113 patients, the study was relatively small. Many participants were so sick that they needed hospitalization, which could have influenced results. Finally, it only studied changes within a year of infection; three to five years later, there may be different markers in the blood, said Seltzer. Patients’ immune systems may not be able to stay overactive indefinitely.

These features suggest potential interventions, wrote Wolfram Ruf of the Center for Thrombosis and Hemostasis in Germany, in a commentary that accompanied the report. Perhaps anti-inflammatory drugs would help. Anti-coagulants might reduce the risk of dangerous blood clots.

“Eventually, the hope is that some of these findings can translate into the clinic, but we are still a ways away from that,” said Peluso. “We need to keep up the momentum to get answers for the tens of millions of people with this disabling condition.”

Now their prized poultry is being delivered, not to the Bay Area’s finest Michelin-starred restaurants, but to the county dump.

Avian influenza has barreled through Sonoma County’s historic poultry region, forcing the slaughter of 1.1 million birds and inflicting heartbreak and economic disaster on the Reichardts and other small family farmers in the once-famed “Egg Capital of the World.”

“We’re still in the midst of wrapping our heads around it all,” said Jennifer Reichardt, 34, a fifth-generation farmer who was required by law to euthanize 4,900 of their beloved “Liberty Ducks” after the virus was detected Dec. 7. “There was never going to be a good time for this to hit, but during the holidays it is especially hard.”

At least six neighboring farms in the Reichardt’s bucolic Liberty Valley, on the western edge of Petaluma, are also afflicted. They include Sunrise Farms, a fourth-generation farm and the largest egg producer in Sonoma County, with an estimated 500,000 birds.

The domino effect on other local businesses, including feed stores and trucking, is incalculable.

“It’s disastrous, a big chain reaction,” said Bobby Falcon of Hunt & Behrens Feed Mill and Store, first opened in 1921 along the Petaluma River, which has lost an estimated 40% of its business selling 24-ton loads of corn and soy-based poultry feed to local farms. “What happens to them falls to us, then the grain brokers. … It filters down about 10 or 11 times.”

A state of emergency has been declared by the Sonoma County Board of Supervisors to help mitigate the effects of the disaster, including assistance for businesses. The county has also designated a special waste section of its central landfill to dispose of the birds, typically killed by sealing up barns and piping in carbon dioxide. State and federal authorities provide expertise, although they’re stretched thin.

Until recently, California’s poultry farms seemed to have been spared from the crisis. Over the past three years, a deadly and highly contagious virus known as H5N1 has circled the globe, taking a staggering toll on birds in more than 80 nations.

After emerging in 2020, the virus triggered major outbreaks in Europe, Africa and Asia. It arrived in the U.S. in January 2022 and stormed through the nation’s largest concentrations of poultry farms in the East and Midwest, pushing up egg prices.

Skipping like a stone over water, the virus landed in Merced County in October, then Petaluma’s Liberty Valley in November.

Despite a swift response — biosecurity measures at farm entrances, the immediate slaughter of potentially infected animals, quarantining of affected farms — the disease has continued to spread.

In only two months, the outbreaks have claimed the lives of an estimated 4.5 million chickens, ducks and turkeys in five California counties. Of these, over 2 million were egg-laying hens, 1.5 million were broiler chickens, and the rest were ducks and turkeys, according to Bill Mattos of the Modesto-based California Poultry Federation.

What’s devastating isn’t just the grim task of killing birds, and huge financial losses, said Mattos. Farmers aren’t allowed to start rebuilding their flocks for 120 days, to prevent repeat infection. Then those fluffy new chicks need weeks to mature. Adjacent farms are under strict quarantine measures, unable to move or process birds, so they lose valuable contracts with buyers. Meanwhile, costs mount.

Poultry was once a prosperous business for this region, where the world’s first incubator was invented in the late 1800s, according to Eric Stanley of the Museum of Sonoma County.

“That really spawned the explosion of the egg industry. There were hundreds and hundreds of farms,” he said. The Petaluma River and nearby railroads offered easy access to affluent San Francisco markets.

But with the state’s road expansion, Sonoma County lost its poultry farms to the much larger and cheaper Central Valley, he said. Trucks’ improved suspension systems could gently ship eggs all over the nation.

The region became famed for what it is today — a monoculture of grapes.

To survive, poultry farmers created a new niche: the Bay Area’s farm-to-table grocery stores and restaurants.

“They are maintaining our legacies and traditions,” said Stanley. “They’re sustaining the heritage things that once gave character to the entire region.”

John Reichardt set out to to raise a meatier, larger and tastier animal. His flock of white Liberty Ducks, a type of Pekin Duck, got off to a modest start in 1992 in his garage, then expanded to a barn, then several barns.

The ducks are antibiotic and hormone-free, with fresh straw for roosting and room to roam. While most ducks are sold at six weeks of age, Liberty Ducks are reared for nine. Lean, but with a distinct layer of fat under the tasty skin, they are prized by restaurants such as Napa’s French Laundry, Berkeley’s Chez Panisse and Kato in Los Angeles.

Experts suspect that the animals were infected by migrating wild birds, although the virus can also be spread by contaminated farm equipment, vehicle tires or shoes.

Sonoma County, with many small and scattered bodies of water, lies along the Pacific Flyway, where populations of migrating birds increase ten-fold in the winter.

“The main reservoir of the virus are waterfowl — the ducks and geese that like the really rich habitat that California supplies,” said veterinarian Maurice Pitesky of the UC Davis School of Veterinary Medicine, who studies the spread of avian diseases.The federal government’s surveillance program has detected the virus in wild birds in 14 California counties this migratory season.

New research suggests that California’s shrinking wild spaces are forcing wild birds to congregate in dairy lagoons, irrigation canals and wastewater treatment ponds, he said. California has lost about 95% of its historic wetlands.

“We’re concentrating waterfowl onto smaller areas, which facilitates disease transmission,” said Pitesky. “This also puts those wild animals closer to our commercial poultry facilities. Potentially infected birds are right next to barns and ranches.”

But the poultry farms have also recently attracted unwelcome human visitors: Berkeley-based members of the animal rights group Direct Action Everywhere, which targets farms with demonstrations and organized incursions. Last month, a member of the group was sentenced to jail for protests at another Liberty Valley duck farm and Sunrise Farms in 2018 and 2019.

Sonoma County farm bureau officials say that the group also trespassed onto those farms in November, within the incubation period of the virus. Activists have not been charged in those events. In an email to the Press Democrat, one member of the group blamed the farms for the outbreaks because of the manner in which the birds are housed and other factors.

“You can’t prove it one way or another — but you can’t disprove it, either,” said Sonoma County Supervisor David Rabbitt, who represents the district where the farms are located. “That’s created a lot of anxiety and frustration.”

Until winter recedes, the virus will continue to haunt Liberty Valley. Fear follows workers as they feed healthy birds, wearing hazmat suits and disposable booties. Once-busy farms lie silent, with “Keep Out” signs banning visitors.

“We are staring down our greatest challenge yet,” said Jennifer Reichardt, who has created a GoFundMe campaign to keep their farm afloat while it works to keep its other properties safe. Supporters have been generous in their response, lifting the family’s spirits.

“There’s a huge industry at risk here of disappearing,” said Reichardt. “We are focusing not only on the preservation of our business but of all family farms in the area. We’re hoping to work together, moving forward, to break through and survive.”

Summer visitors driving to Yosemite National Park will soon find out, when the park moves to a reservation-only entry system, like movie theaters and theme parks.

Overwhelmed by last year’s crush of visitors, the popular park will also require advance booking of vehicles on spring and autumn weekends, according to a plan announced by the Park on Wednesday. Reservations will open at 8 a.m. on Jan. 5.

The plan is based on the past four years of experience, as well as public feedback and lessons learned from other national parks, said Superintendent Cicely Muldoon.

Reservations were required during the COVID pandemic, then again in 2022, from March 23 to Sept. 30, due to a number of construction projects that restricted access to some popular areas of the park that year.

The limits on visitors enhanced the wilderness experience, rather than detracting from it, she said.

“The people who were able to get reservations absolutely loved it,” experiencing giant sequoia groves, wilderness and waterfalls free of stress and congestion, said Muldoon. “It was a game-changing experience — how one would want to visit a national park.”

When the system was suspended last summer, chaos ensued, Muldoon said. Huge crowds caused such long waits to get into the park that some visitors were forced to turn back. Cars were parked illegally in traffic lanes, on grass and between rocks, with lines stretching on for hours. The havoc was compounded by deep Sierra snow and a shortened season, concentrating visitors into peak summer months.

“It was back to the bad old days,” said Muldoon. “It was really terrible. Parking was off-the-charts crazy.”

Walk-in visitors do not require a reservation, but for travelers who drive, reservations are required for entry on weekends from April 13 to June 30; every day from July 1 to Aug. 15; and on weekends from Aug. 16 to Oct. 27. They must be booked through the website Recreation.gov/timed-entry/10086745.

Visitors will pick from two types of reservations: Reservations valid for a full day, or reservations valid for entry any time after noon. Both reservation types — full day and afternoon — are valid for up to three consecutive days, including the arrival date.

There will still be opportunities for casual drop-ins. Reservations aren’t needed to enter the park after 4 p.m. – or before 5 a.m., if you’re an early bird.

Visitors with in-park lodging or campground reservations, wilderness or Half Dome permits, or who enter the park on buses or on commercial tours do not need a reservation.

Afternoon arrivals and additional full day reservations may be added one week in advance — for example, reservations for a Sept. 30 arrival date will be added on Sept. 23.

Reservations are also required to enter Yosemite on the weekends of Feb. 10-12, Feb. 17-19, and Feb. 24-26, during peak time for the “firefall,” a waterfall streaming down the face of El Capitan and illuminated by a February sunset. The firefall, which has become a massive draw for photographers, occurs in February when the setting sun hits Horsetail Fall at just the right angle. Campsites usually available on a first-come, first-served basis will also require reservations.

Several other national parks are taking a similar approach, such as Marin County’s Muir Woods, Arches National Park in Utah, Rocky Mountain National Park in Colorado, Acadia National Park in Maine and Glacier National Park in Montana.

The online reservation system has raised concerns that it will discourage visitors such as the low-income and historically marginalized communities that the Park Service is working hard to attract.

Many people don’t have a job or lifestyle that allows them to plan six months in advance for a vacation, say critics.

But Mark Rose, manager of the National Parks Conservation Association Sierra Nevada Program, commended Yosemite’s strategy, saying that all visitors to the park, “especially those from underrepresented communities, deserve a positive experience, not gridlock traffic.”

“We strongly support the return of Yosemite’s reservation system in 2024, particularly following a summer where no limitations at park gates led to frequent hours’ long traffic jams, Valley closures, and untold damage to natural and cultural resources,” he said. “Beyond 2024, we urge the Park Service to move once and for all towards a permanent reservation system.”

Yosemite is working with its nonprofit partners to publicize the reservation system in Spanish and do outreach in the Central Valley, said Muldoon.

“We need to find a system that is equitable,” she said. “We really want to expand that effort.”

The reservation requirement may enhance the experience for visitors, but it could mean less business for the shops and lodges that surround the park, according to the Yosemite Mariposa County Tourism Bureau.

Tony McDaniel of the Tourism Bureau said it plans to promote other activities in the region, such as visiting Gold Rush history.

“When tourism is slowed by the reservation system…people aren’t filling our hotels, and they’re also not supporting other small businesses,” he said. “Our businesses located outside of the park in Mariposa County are trying to basically make up an entire year’s worth of profit with generally just the summer periods. So when the park puts a reservation system in place, those businesses are left trying to adapt.”

“We’ll help people understand there’s more to see in Mariposa County than just in Yosemite,” he said.

Now — full of promise and peril — psychedelics are undergoing a makeover. Chemical neuroscientists, many based in Northern California, are redesigning the structures of psilocybin, ketamine, MDMA and other powerful drugs to concoct compounds that they hope will offer mental health benefits with fewer risks.

With advanced tech tools and a deepened understanding of brain chemistry, scientists say the new drugs might succeed where conventional therapies have failed, treating post-traumatic stress disorder, anxiety, depression, addiction and other devastating mental health problems.

“Our goal is to make medicines that are derived from psychedelics that are safer and gentler, more effective and more accessible,” said Matthew Baggott, former director of data science and engineering at Genentech, whose Palo Alto-based startup Tactogen has patented several novel MDMA, or “Ecstasy,” molecules that offer spiritual and personal insights with less heart-racing anxiety and euphoria.

At the new UC Davis Institute for Psychedelics and Neurotherapeutics, director David Olson is tweaking psychoactive drugs to spur neural growth and rewire the troubled brain without triggering hallucinations or adverse effects. His biotech startup, Delix Therapeutics, has built a portfolio of more than 2,000 non-hallucinogenic compounds.

Stanford University School of Medicine investigators Dr. Boris Heifets and Dr. Rob Malenka have pried apart MDMA’s therapeutic and addictive traits, distinguishing the different molecular pathways behind the drug’s sociability and abuse potential.

RELATED: Psychedelic drugs: Follow the money

“Can we deconstruct these drugs — basically, take them apart and put them back together — so that they have one of these effects and not the other?” said Heifets, assistant professor of anesthesiology, perioperative and pain medicine.

Separating the agony from ecstasy “would be more helpful and less harmful,” he said.

So far, researchers have managed to demonstrate such decoupling only in rodents. The research in people is embryonic, so we don’t yet know whether drugs can be purely therapeutic.

Compared to modern medicines, the classic psychedelics are elderly. MDMA, or “ecstasy,” was synthesized in 1912 when Woodrow Wilson was president. Swiss chemist Albert Hofmann isolated LSD from grain fungus in 1938 and psilocybin, found in “magic mushrooms,” in 1958. DMT was isolated from the root bark of a tree in 1946. Ketamine, an anesthetic, was made in 1962.

But therapeutic research slowed in the mid-1960s amid President Nixon’s “War on Drugs,” tightened regulations and disappointing clinical trials.

Psychedelic drugs have long been known to be among the most powerful substances to act on the human brain. Emerging science shows why: They stimulate a receptor in the brain known as 5-hydroxytryptamine 2A (5-HT2A), as well as other lesser known brain receptors. There is evidence that they can produce changes in brain architecture by spurring regrowth of damaged neural circuitry and new connections between synapses.

But there are major downsides. Some cause life-threatening heart problems or body overheating. Perception-distorting effects may make them distressing, even dangerous, for people with a predisposition to mental illness. Patients on anti-depressants such as Prozac also risk adverse reactions. Some of the drugs are hard to administer and persist longer than needed.

An off-duty Alaska Airlines pilot charged with trying to shut off the engines of a flight in October told investigators that he had been sleepless and dehydrated since he consumed psychedelic mushrooms about 48 hours before boarding. He had struggled with depression for months, he said.

“They have tremendous potential, but they’re very crude tools,” said Heifets.

Psychedelics are classified as Schedule I substances, illegal except under tightly regulated circumstances, so researchers have faced legal restrictions and professional stigma.

But now, with growing frustration over shortcomings of conventional therapies, there are incentives to innovate.

Private investment into psychedelic research and development has surged, supported by an FDA “breakthrough therapy” designation for clinical trials of psilocybin for depression in 2018. Next summer, the FDA is expected to approve MDMA as a treatment for PTSD, based on clinical trial results at UC San Francisco in a study by the San Jose-based Multidisciplinary Association for Psychedelic Studies.

Philanthropic, institutional and government funding of research has led to the creation of academic centers for psychedelic science across the country. In 2020, the Defense Advanced Research Projects Agency (DARPA) directed $27 million to a 30-person lab at the University of North Carolina at Chapel Hill, where professor Dr. Bryan Roth uses robots, computational chemistry and electron microscopy to identify thousands of new chemical structures.

More than 100 companies are focused on psychoactive drugs, according to patent attorney Graham Pechenik of the San Francisco-based Calyx Law.  Five years ago, only a few dozen patent applications had been submitted for psychoactive-related products, he said. Now his Psychedelic Alpha patent tracker counts more than 1,000.

“I really thought that psychedelics were going to just stay underground forever or maybe stay this weird area of academic research,” said Brom Rector of Empath Ventures, which invests in early stage psychedelic-focused companies. “Over the last few years, all that’s changed.”

Meanwhile, the cultural conversation around psychedelics has begun to shift. Oakland, San Francisco, Santa Cruz and Berkeley have decriminalized “natural” psychedelics. Gov. Gavin Newsom vetoed a bill that would have allowed personal possession of psychedelic mushrooms in California, asking lawmakers to send a version next year with therapeutic guidelines — suggesting that he might be more supportive of medicinal use than decriminalization.

Scientists say research needs to keep up. “The psychedelic landscape is moving very, very quickly. … People are starting to use them without the appropriate guardrails in place,” said Olson. “We still need to understand how they work.”

To make them safer, scientists enlist one of two strategies.

Some are modifying the chemical structures of existing drugs, such as swapping an oxygen atom for a carbon atom. Others are building new drugs from scratch, assembling them like Tinker Toys. They might select the components that are needed to promote neural growth, for instance, but delete those linked to hallucinations.

Updates are long overdue, said Rector.

Existing psychedelics “are the best drugs from almost 100 years ago — the Ford Model T of psychedelics,” he said. “I want to see what the Tesla Model S in psychedelics is going to be like.”

But biotech startups, academic scientists and investors say that research into psychedelic drugs starts with a major advantage: These substances are already known to work.

The goal is simply to improve upon them – so they’re safer, more effective and faster-acting. Someday, perhaps, psychedelic-like drugs could treat mental illness for a fraction of what it costs to do therapy with conventional tools.

RELATED: New psychedelic-like drugs: All treatment, no trip?

Three drugs — MDMA, psilocybin, and ketamine — are the furthest along in clinical development for mental health disorders, according to Dr. Boris Heifets of the Stanford University School of Medicine.

Investors are already betting tens of millions of dollars, sensing the opportunity to replace drugs like Prozac, Zoloft and other selective serotonin reuptake inhibitors. Prescription sales for these depression treatments are estimated to be $50 billion a year globally, while the mental health market is worth about $100 billion in annual sales.

Venture-capital funds that are focused on early stage psychedelic companies include Empath Ventures in Los Angeles, Tabula Rasa Ventures in New York City; PsyMed Ventures in San Francisco.

“It’s now socially acceptable for a respected scientist to study psychedelics and run a clinical trial,” said Brom Rector of Empath Ventures. “And it’s acceptable for a serious venture capitalist to put money into a psychedelic company.”

Over 1,000 patent applications have been supported in this new field, according to patent attorney Graham Pechenik of San Francisco’s Calyx Law. According to his patent tracking website, more than 400 involve the drug psilocybin; 250, ketamine; 200, ibogaine; 200, LSD; 200, DMT, 150, MDMA, and 100 for a drug called 5-MeO-DMT. Because patent applications are only made public 18 months after submission, the real number is likely far higher, he added.

A recent report from Data Bridge Market Research projects that the global market for pharmaceutical psychedelics will reach $6.4 billion by 2030.

Some companies merely tinker with existing agents, aiming to fine-tune them. But others are developing entirely new chemical entities. Using computers, scientists model their structure. Then they send instructions overseas, usually to India, where the molecules are produced. Once returned to the U.S., they are tested with so-called screening assays to identify any promise.

Companies working with psychedelic drugs include:

• Arcadia Medicine, San Francisco
• Atai Life Sciences, Berlin, Germany
• Beckley Psytech, Oxford, England
• Bright Minds. New York City
• Compass Pathways, London, England
• Cybin, Toronto, Canada
• Delix Therapeutics, Boston
• Freedom Biosciences, San Francisco
• GH Research, Dublin, Ireland
• Gilgamesh Pharmaceuticals, New York City
• Mind Medicine, New York City
• Multidisciplinary Association for Psychedelic Studies, San Jose
• Reunion Neuroscience, Toronto, Ontario, Canada
• Tactogen, Palo Alto
• Usona Institute, Madison, WI
• Viridia Life Science, New York City

It is also a blank slate, offering a fresh start to a young and energetic generation of newcomers — who vow to build a new Paradise, a smarter community that will never burn again.

“We get to watch it transform,” said Goodlin, 41, who left the comfort of suburban Colorado Springs with her husband and four children to move back home to Paradise.

“We have come so far,” she said. “And we still have so much to do.”

Five years ago, all seemed lost. On the morning of Nov. 8, 2018, the entire town of Paradise was quickly engulfed in flames as residents frantically rushed to escape the Camp Fire, the deadliest and most destructive wildfire in California history.

From the moment high winds broke a worn and aged C-hook on a PG&E transmission tower, causing a 115-kilovolt line to drop onto dry brush and ignite and quickly spread, Paradise became a global symbol of risk, tragedy and negligence.

When the fire was finally contained 18 days later, 85 people had died, about 11,000 homes were destroyed and 153,336 acres were burned, shattering lives and livelihoods. An astonishing 90% of Paradise’s housing was gone. Much of the nearby rural communities of Concow, Butte Creek Canyon and Magalia also were lost.

As climate change has intensified the ferocity of California’s wildfires, many looked to Paradise and asked: Is it time to retreat, not rebuild, from areas that are especially flammable?

Instead, Paradise is changing its strategy. It will rebuild differently, safely. Atop a windswept ridge between two wild canyons, the town is preparing for a hotter, drier climate an inspiration for other California towns at risk of nature’s whims and man’s mistakes.

Its people are changing, too.

A year after the fire, Paradise was such a forbidding hellscape, and residents’ plans for recovery were so tangled in red tape, that the town’s population had dropped from 26,423 before the blaze to just 4,590. Now the town has 9,142 people, about one-third of its former population. If the pace continues, the town expects to fully recover within 20 years.

Two-thirds of this year’s arrivals are new residents, up from one-third in 2019, according to the Paradise Ridge Chamber of Commerce and CSU Chico research. Some hail from crowded California cities; others are out-of-staters, seeking an affordable California dream. On average, they tend to be young. They come full of hope and free of trauma.

“We had never heard of the fire,” said 28-year-old Taylor Tanner, who moved to Magalia in 2021 with her husband Kristofer and two young sons from west Texas.

“Since when does a town get to be completely brand new, in this day and age? Built from the ground up, to be whatever we want it to be?” she said.

This year, more than 400 ballplayers joined the town’s Little League, up from 145 after the fire. The new “Moms Of the Ridge” social group, founded by three young parents two years ago, has 1,300 members. While overall school enrollment remains far below pre-fire levels, the elementary school is bursting at the seams. To prevent crowding, administrators are considering moving older students to the junior high campus.

“Our new families want to get involved in the community,” said Little League president Liz Brewster, who led the post-fire effort to replace burned backstops, bleachers, equipment sheds, fences and fields. “And that’s creating more of a family environment than what we had before the fire.”

Popular stores like Ross, Big Lots and Tractor Supply have opened, buoyed by an economy that until recently was reliant on federal and state grants, donations, insurance payouts and PG&E legal settlements.

But the empty lots and desolate roads are ghostly reminders of neighbors who will never come back.

About 30% of the town is rebuilt. Heartbreak, rising construction costs, insufficient insurance coverage and meager PG&E payouts have kept many people from returning — especially retirees of modest income.

The only hospital in town has permanently closed, leaving residents with no emergency care. The beloved Paradise Cinema 7 is gone, after a long legal battle with its insurer. Gas stations, McDonalds, Burger King and many modest mom-and-pop stores have vanished. The historic Gold Nugget Museum, still waiting for its PG&E settlement check, is storing precious artifacts in cargo containers until it can renovate an old auto transmission shop.

“You can tell, almost by looking at someone, whether they were here,” said survivor Joan Ellison, 68, who is living in a Chico apartment while slowly rebuilding her home. “Because we know something that no one else knows.”

“Our pine trees interlock roots to be stable. They’re upheld by each other. And that’s what we’re doing,” she said.

The first goal was cleaning up the community cutting trees, fixing the water supply, removing toxic debris and dragging away an estimated 20,000 charred husks of cars, some of them deathtraps. At a former Bank of America, the Building Resiliency Center opened to provide one-stop shopping for all construction information. Nine different low-cost floor plans, free and pre-approved by the city, are offered by the Rebuild Paradise Foundation.

The early arrivals were overwhelmingly long-time residents, not newcomers, according to research by CSU Chico geographers Jacquelyn Chase and Peter Hansen. The first two homes were completed in July 2019, nine months after the fire.

Of those who returned promptly, almost all were well-insured. The modest 1960s-era house owned by town councilman and former Mayor Steve “Woody” Culleton, covered by Allstate, had terrible insulation, electric baseboard heat and the dense shade of 16 pine trees. His replacement home, built to modern standards, is larger and more elegant, with solar panels, a sunny porch and a vegetable garden.

Others, like Ellison, said they felt too numb to think straight. Once they got on their feet, things were complicated and expensive.

Recovery was slowed by protracted insurance negotiations. Then COVID hit, and with it supply chain delays in getting even the most basic building materials. PG&E payouts were too little, too late, averaging only 60% of what most residents anticipated. There was competition for contractors. Prices skyrocketed.

“I had everything ready. Everything was approved. I was ready to go,” recalled Ellison. “But costs had tripled. It was horrible. I couldn’t build.” Now, with the help of a nonprofit foundation, she’s finally back on track.

Developers began showing up about a year or two after the fire, buying unwanted parcels for $20,000 to $60,000 each. Because homes are on septic systems, no large subdivisions are planned.

The new Paradise will likely have more apartments, because there is public and private funding for affordable multifamily housing units. About 180 permits have been issued for multihousing projects representing hundreds of units. One project, Paradise Community Village, serves only low-income families.

Almost all of the town’s 32 mobile home parks remain unbuilt. Because they are privately owned businesses, there’s little government aid, said Colette Curtis, the town’s director of Recovery and Economic Development. Most were not adequately insured to rebuild their roads, septic tanks and other infrastructure, she added.

In the surrounding neighborhoods, lots will likely be larger, as residents buy empty adjacent parcels. With lower density, evacuation should be safer, said Goodlin, whose family lived in a trailer until builders finished their custom-built home with an interior sprinkler system, fire-resistant construction and a vast perimeter of defensible space.

New homes are more spacious, on average, than those in old Paradise. Before the fire, 12% of homes had one bedroom; now only 3.6% do. Nearly 70% of new construction features three or more bedrooms. This includes many mobile and modular homes, which represent one-third of all new permit applications.

Downtown will be smaller and more walkable, with new sidewalks, lighting and landscaping, said Mark Thorp of the Paradise Chamber of Commerce.

Many businesses have been waiting for residents to return before committing, he said.

“We’ve had to put a lot of emphasis on the residential sector in order to get the numbers up to sustain businesses,” he said.  “Now, they’re seeing the market. It’s a good feeling to say ‘Let’s get back on this horse.’ It’s a rejuvenating purpose.”

To fortify itself against future disasters, the town has launched 37 projects, such as:

• An emergency notification system. Twenty-one sirens atop steel towers, disguised as Douglas fir trees, emit one minute of loud “Hi-Lo” warning sounds followed by evacuation instructions.  The system can be controlled manually, over the internet or by satellite. Power is hard-wired underground, but each siren also has a solar panel. Many have cameras.
• Widened evacuation routes. One of the major corridors, Pentz Road, is getting a $73 million widening, with a new two-way left turn lane and bike path, which can double as an evacuation route. Skyway, another artery, will be widened to increase its capacity.
• Underground utilities. So far, PG&E, Comcast and AT&T have jointly trenched more than 80 miles, reducing the risk of wildfire ignition, Public Safety Power Shutoffs, and boosting evacuation safety.
• Linked road segments. In a $200 million project, the town aims to connect three of the town’s longest dead-end roads, where people were trapped and died, to a major corridor.
• Toughened residential building codes. During the fire, homes that were built to tough “Wildland Urban Interface” standards were more likely to survive, so that’s the new code. To be extra safe, some homes have steel frames or insulated concrete.
• Fuel breaks. The town hopes to buy some properties on its eastern edge by the Feather River canyon to create buffer zones of low vegetation, which could also be used for hiking trails.

But the dream isn’t just to survive — it’s to thrive, say civic leaders.

A vast fiber optic network could bring high-speed internet to town, and a sewer project will send wastewater from downtown businesses to Chico’s treatment plant, eliminating the old septic systems that have limited growth.

“It would be ‘backward thinking’ of us to do a replacement of our old 1940s, ’50s and ’60s infrastructure,” said Thorp. “We’re in the 21st century.”

Goodlin, who grew up in Paradise, rushed from Colorado after the fire to say goodbye to a town that had surely died. But when she saw it stir to life, her heart softened. Her husband Brett, a CPA, supported the decision to move.

“It’s hard. We feel like pioneers,” said Goodlin, who now leads the Rebuild Paradise Foundation. “We could see the opportunity for a different life for our kids. There’s a realness to living here. We thought: ‘This is where we belong.’ “

Her yard has chickens, nectarines, apples, coyotes and an occasional mountain lion. Her children attend a state-of-the-art high school, with a modern library and science buildings, a new 1,500-seat gymnasium, six new tennis courts and a softball complex.

She is proud that a once-devastated community has become a giant workshop to test solutions to a hotter, drier future.

“At first, people asked: ‘Can this town recover? Should we just leave it? This is too much,’ ” she said.

“Then enough people said, ‘No, we can do it. It’s going to be super hard. But we’ll take it one step at a time.’”

The results — whether the men are cured or not after the one-time intravenous infusions this year — have not yet been disclosed by the San Francisco biotech company that created the technology based on Nobel Prize-winning research by UC Berkeley’s Jennifer Doudna.

But the potential treatment, called EBT-101, is safe and caused no major side effects, Excision BioTherapeutics reported at a meeting in Brussels.

Six more men will be treated, perhaps some at UC San Francisco, with higher doses. Participating in the research program is potentially risky: Participants stop their protective anti-HIV drugs for 12 weeks after gene-editing treatment to see if the virus is gone. Data will be presented at a medical conference next year, according to the company.

“We are opening the door for how this new drug will work and what potential it has for people living with HIV,” said Dr. William Kennedy, Excision senior vice president of clinical development. “Ultimately, we see this as a fundamentally new approach.”

The novel strategy could potentially treat other chronic infections where the virus hides latent, such as hepatitis and herpes, he said. It leaves human DNA intact.

“We were super excited about this, and to get the chance to be among the first to do human studies of gene editing for a cure,” said Dr. Priscilla Hsue, professor of medicine and principal investigator for the study’s clinical trial site at UCSF. “If we can permanently remove viral DNA, the thought is, people would get this infusion and then be done.”

EBT-101 is designed to find the specific viral sequences so that it doesn’t cut human DNA. The CRISPR-based therapy uses an empty virus to deliver the “guide RNA” that marks where to cut. An enzyme called Cas9 acts like scissors. The therapeutic solution is given intravenously.

It received the FDA’s “fast track” designation last July after experiments showed success in animals. A single injection safely and efficiently removed SIV, a virus related to HIV, from the genomes of rhesus monkeys. In earlier work, it removed HIV from nine of 23 mice.

But there is a big leap from promising results in mice to success in humans. In addition to UCSF, patients will be recruited at Quest Clinical Research in San Francisco, Washington University in St. Louis and Cooper University in Camden, New Jersey.

In the four decades since the AIDS virus was isolated, treatment has transformed its care. If taken every day, powerful antiretroviral drugs can suppress the virus, controlling illness. Medicine can also prevent infection.

But a cure is needed to end the pandemic. Worldwide, nearly 39 million people are living with HIV. About 77% of them are receiving treatment.

There have only been three known cases of an HIV cure so far. Two were men who received bone marrow transplants from donors who carried a mutation that blocks HIV infection. The third was a woman who received a transplant of umbilical cord blood. But all three treatments were targeting cancer, so this is not a practical option for the average HIV patient.

“The future of so many lives depends on another breakthrough,” said Mark S. King, an Atlanta-based HIV/AIDS activist and author of the book My Fabulous Disease who has lived with the virus for nearly 40 years.

“A lot of people think that this was all rectified when we got successful treatments,” he said. “But the difference between a treatment and a cure, or a vaccine, is profound.”

Excision BioTherapeutics was founded on work in the lab of Kamel Khalili, a professor at Temple University in Philadelphia and director of its Center for NeuroVirology and Gene Editing.

Its research is supported, in part, by the taxpayer-supported California Institute of Regenerative Medicine. The early results of its study were presented at the European Society of Gene and Cell Therapy on Wednesday.

CRISPR gene editing, an ingenious system discovered by Jennifer Doudna, a biologist with UC-Berkeley’s Innovative Genomics Institute, can cure genetic disease by using little molecular scissors to cut out a piece of a person’s DNA. It is now being used to treat several diseases, such as sickle cell anemia, nerve disease and congenital blindness.

Scientists wondered: Could CRISPR cure HIV by cutting the virus’s DNA? Excision’s approach cuts the virus in two places, removing genes that are essential to replication.

“This is an exceptionally ambitious and important trial,” said Fyodor Urnov, professor of molecular and cell biology at UC-Berkeley and a gene editor at IGI, in an email. “It would be good to know sooner than later” if it works, he said, “including, potentially, no effect.”

Initial research in Khalili’s lab showed that CRISPR could find and destroy the HIV genes in cells.

The results were welcomed with caution by long-term survivors such as King. “Am I intrigued? Yes. Wary? Absolutely. We have been here before, many times. We’ve heard of a lot of promising developments over the years, only to have the rug pulled out from us — because of the vexing nature of how HIV operates in the body.”

The reason that HIV has been so tough to eradicate is that it hides in our cells, said Dr. Jyoti Gupta of the PACE Clinic at Santa Clara Valley Medical Center, which specializes in HIV care.

“The virus is very smart,” she said. “It integrates into the host genome of our immune cells, which are supposed to protect us from infection. It just lies there, hiding.”

“As soon as someone stops the therapy, the latent virus starts replicating again, within days,” said Gupta. “Then there’s virus everywhere.”

Patients in Excision’s trials will be monitored for 15 years, said Kennedy.

Even if it just stops replication for awhile, that’s a benefit, said Gupta. “Less is more. So if a patient can come in for an infusion once a year, for instance, and the virus won’t resurface for a year, that’s reasonable.”

The hope is that Excision’s therapy could become a lifelong cure, freeing patients from daily pill-popping

“Scientists tell me that this is going to be part of a cure some day,” said Berkeley-based AIDS activist Matt Sharp, 68, who has lived with the virus for 38 years. “And I shrug my shoulders and say, ‘Here we go again.’ “

“Now we just have to get the research done,” he said.  “We’ve got to have hope, because the epidemic isn’t over.”

Born with a deadly blood disease, the Finlayson’s daughters — Ada, 9, and Lily, 12 — are the first patients on the West Coast to receive a new gene therapy offered by UCSF Benioff Children’s Hospital Oakland.

Already, Ada is already feeling better 10 weeks after receiving her stem cell transplant. Lily started treatment last week. Both have 90% chance of a permanent cure.

“It’s science, and it’s a miracle,” said their mother Alissa, sitting in the small yard of their guest home in downtown Oakland, far from their small mountain town of Kalispell, Montana.

The children were born with beta thalassemia, a common hereditary red blood cell diseases in China. Unable to create normal blood cells, they’ve needed six-hour-long blood transfusions every 21 days, an intense treatment that carries risk and requires constant monitoring.

Because Chinese orphanages can’t provide treatment, both girls were destined to live short lives.

Then the family found that UCSF’s Oakland hospital is one of three sites in the U.S. to offer the initial test of the therapy, Zynteglo. Now that Zynteglo is FDA approved, the hospital is among 15 in the nation authorized to provide care. Stanford’s Lucile Packard Children’s Hospital, Loma Linda University Children Hospital and Seattle Children’s Hospital will also offer the treatment.

The therapy is a one-time treatment that works by using an engineered virus to deliver a healthy gene into patient cells. It’s not the same as CRISPR, which uses gene editing to fix existing genes. That process is still under review and has not received FDA approval.

“The point of the treatment is to stop those transfusions,” said Dr. Mark Walters, a hematologist and director of the hospital’s Pediatric Blood and Marrow Transplant Program. Walters will follow the girls and other patients for 15 years to see if there are long-term complications, or if they remain free of disease and can be considered truly cured. Other patients are in the hospital’s pipeline.

Beta thalassemia is caused by a single mutation on the gene for hemoglobin, the protein in red blood cells that carries oxygen to tissues. Children develop life-threatening anemia. They can’t gain weight or grow properly.  They suffer organ damage.

By fixing the underlying genetic problem, the new treatment buoys hopes for an estimated 1,300 to 1,500 patients — and opens up the possibility of treating other simple inherited disorders.

Scientists say this approach will be a crucial part of 21st century medicine. An estimated 400 million people worldwide are affected by one of the 7,000 diseases caused by mutations in a single gene. ‌

“It’s incredibly exciting time, as we harness what we’ve learn about genes and then how to fix them,” said Walters.

“This is just one disease we’re treating with the gene therapy,” he said. “There are lots and lots of others to work on. All the lessons we’ve learned about genetics are coming to fruition.”

These customized treatments remain challenging to build and are profoundly expensive. Zynteglo, made by Massachusetts-based biotech company bluebird bio, costs $2.8 million for a single-use vial, making it one of the most expensive drugs in the world.

But money is saved by a lifetime without ongoing care, which can cost many millions of dollars.

Devout Christians, the Finlaysons married in their early 20s and soon bore two biological children in the picturesque 1800s-era town near Glacier National Park, with mountains, alpine trails and lakes filled with trout. Clint, 41, is an engineer; Alissa, 38, is a music teacher who homeschools their children.

Seeking to grow their family, they shared a dream of adoption. They agreed to welcome a child with any medical condition.

“It’s just something that you figure out,” said Alissa. “We have very strong faith that God is going to put the child in our path that he wants us to adopt.”

Charmed by Lily’s cherubic photo, they brought her home.  About a year later, they received a call asking if they would consider adopting a second girl, Ada, with the same medical condition. Their answer was a definitive “Yes.”

They’re now inseparable. Lily is quiet, thoughtful and strong. Ada is an impish ball of energy.

To keep them healthy, “it’s like a weight you put on,” said Clint. “But after awhile, you forget it’s there.”

When the couple learned of the promise of gene therapy, they rushed to put their names on the hospital’s wait list. Friends’ daughters, also adopted from China, had completed the clinical trial and were thriving.

The call came as Alissa was sitting on the family couch, teaching her brood. “I recognized the 510 area code,” she said. “I didn’t hesitate. I said: ‘Yes. When can we come?’ “

“We believe that God has paved a way for us to be here,” she said, pausing for the roar of a passing BART train. “We miss home, but we love how knowledgeable the people here are, and how they treat us as a family.”

Ada went first. From start to finish, the process took four months.

First, her stem cells were collected from her blood. Using a virus, healthy copies of the hemaglobin gene were inserted into these collected cells, then grown for three months.

Chemotherapy killed off the bad stem cells in her bone marrow to make room for the new healthy cells. Her hair fell out. The cells were infused into her body, and found their home in her marrow. They are now beginning to pump out normal hemoglobin.

The beauty of this approach is that patients don’t reject their own bone marrow. And there’s no risk of a dangerous complication caused when foreign cells attack the body’s own tissues.

“You just do the next thing, and the next thing leads you to something else,” said Clint. “Then eventually, holy cow, you’re on the other side of it.”

For the first time in her life, Ada needs no transfusions. While her hemoglobin levels won’t fully stabilize for a year, her spunk is emerging as the disease departs.

Lily’s treatment, delayed by a cell manufacturing error, has now started. It was a major disappointment, because the girls could not be treated together. And instead of staying in Oakland for four months, the family must be here for eight.

The Finlaysons also struggled to gain insurance coverage, and feared medical debt. After two months of daily phone calls with Aetna, coverage is now guaranteed.

“You feel these painful moments and you just want to give up sometimes,” said Alissa. “But we’re blessed to be here. We have an army of family, friends and our church praying for our entire family.”

Impatient with her family’s tale, Ada bounced over, announcing “This is boring to listen to!”

“I don’t really think the magnitude of this has hit them,” Alissa said, offering a hug. “They think getting cured is totally normal.”

During the early stages of her illness, she created complex visual interpretations of classical music, such as George Gershwin’s Rhapsody in Blue and Maurice Ravel’s Boléro. Then she shifted to painting even more abstract concepts, such as numbers.

A recent UC San Francisco-led study of brain scans of Adams and other patients with the deadly “frontotemporal” variety of dementia has revealed the underlying mechanism behind this mysterious shift in creative expression.

As the brain region responsible for language is dying, it activates the visual processing area that drives creativity, according to Dr. Bruce Miller, the senior author of the recent study, a collaboration of 27 scientists published in the journal JAMA Neurology.

“This is a way that the brain copes with an insult,” said Miller, director of the UCSF Memory and Aging Center. “It mobilizes whatever circuits are still available and untouched.”

Similar yet different changes may help explain the mood and behavioral shifts sometimes seen in patients who have had other brain injuries or illnesses, such as stroke or Alzheimer’s disease, he said.

The UCSF research also offers insights into the workings of the healthy brain, engaged in a constant dance — some circuits turning on and others turning off.

On Friday night, Adams’ story — which, uncannily, parallels a similar burst of creativity and mental decline in the composer Ravel a century earlier — will be told on stage at the San Francisco Conservatory of Music in a one-night performance of the play UnRavelled. The performance, produced by the Association for Frontotemporal Degeneration, will be followed by a 30-minute panel discussion on creativity and brain science by UCSF’s Miller and other experts.

“It is a very beautiful, sad story that captures the birth of something extraordinary,” said Miller.

Frontotemporal dementia (FTD), which affects about 60,000 Americans, is different from Alzheimer’s disease. It typically affects people younger — in their 50s and 60s — such as actor Bruce Willis. It doesn’t affect memory; rather, it changes behavior and language. It is incurable, and there are no approved therapies to slow or alter its course.

Scientists previously thought that neurodegenerative diseases hit the brain everywhere, at once. Now they know that they start in a very small and specific region of the brain, targeting certain cells. But over time, the damage spreads and is lethal.

Misfolded proteins build up in the frontal and temporal lobes, disrupting and eventually killing cells called von Economo neurons. This part of the brain does a lot of things — but its most important job is language and social behavior.

A small subset of patients with a specific variant of FTD show a burst of visual creativity as they decline — painting or making montages, pottery, sculpture, jewelry, quilts, even welding colorful insect-like creatures. It is not known why some patients develop creativity and others don’t.

Patients who were artists become more visually obsessed. But even people with no previous interest in art become engaged in their new hobby for many hours a day.

When healthy, UCSF patient Victor Wightman had no interest in art; he enjoyed running, swimming and basketball. But at age 48, a year before his FTD diagnosis, he began painting images of animals and cartoon characters in vivid, almost electric, colors.

Another patient, Jancy Chang, was a talented Santa Cruz artist and teacher. After retirement at age 52 due to declining language skills, her paintings became much bolder, wilder and more original.

A third, Dick Smith, became a constant walker as he declined. He wasn’t experienced in art, and was too restless to focus. But as he circled, caregivers handed him a paint brush. With each restless loop, his colors changed.

Such research can accelerate the search for therapeutics and improve caregiving, said Susan Dickinson, CEO of the Association for Frontotemporal Degeneration.

“Everything we learn about the fundamental aspects of what this disease is, and how it affects the brain, will help us design strategies to intervene, or even prevent, the disease process,” she said. “And it offer clues for ways to help families stay connected with the people they love, helping maintain the quality of life as long as possible.”

“Even if patients don’t become beautifully creative, like Anne Adams did,” Dickinson said, “are there ways to help them stay active and feel purposeful?”

The link between FTD and new artistic talent was first described by Miller in 2007 in the journal Brain. The new UCSF study, led by behavioral neurologist Dr. Adit Friedberg, sought to understand why.

The team analyzed the records of 689 FTD patients and identified 17, or 2.5%, who had experienced a burst in visual creativity at the start of their dementia. It compared the brain scans of these patients to matched patients who did not show increased creativity, as well as the brains of mentally healthy people.

The scans revealed that the region of the frontal cortex, responsible for language, had shrunk in visually creative patients, while areas in the back of the brain on the right side, devoted to visual and spatial processing, were more active.

In healthy people, these visual regions may be inhibited by the dominant frontal cortex, said Miller. But when damaged, creativity is released.

This shift seems to reflect “neuroplasticity” — the ability of the brain to form new connections or reorganize itself, the study concluded. It also found an enlargement in the area of the brain that involves movement of the right hand.

“When one part of the brain doesn’t work as well, other areas may be able to work better than they did before,” said Miller.”

Periodic brain scans at UCSF offered a remarkable glimpse of changes in Anne Adams, from her diagnosis in 1997 until her death in 2007.

Trained in physics and chemistry, she earned a PhD in cell biology while raising four children. She taught and did research at the University of British Columbia, then left her career to take care of an injured son. To pass the time, she turned to art. Her initial works were simple drawings and architectural watercolors.

“She was very bright, and she was also artistic,” said her widower Robert Adams, 83, a professor emeritus of math at the University of British Columbia.

Increasingly drawn to repetition and abstraction, her work turned more vibrant. In a rendering of the mathematical ratio pi, she mapped a vivid matrix of its first 1,471 digits.

Her most ambitious piece, which took three months, deconstructed Ravel’s famous song Boléro. The insistent, rhythmic plod of the music — all 340 bars — was transformed into symbols and colors. The A note was painted silver; A-flat, copper; B, leaf green; B-flat, metallic green, and so on.

Just like Boléro‘s melody, her symbols repeated and repeated. With each crescendo, the rectangles grew taller.

Scientists now suspect that in the late 1920s, when Ravel composed Boléro, he also suffered from FTD. A man of order and perfection, his behavior turned erratic. Within several years, he lost the ability to translate music from his mind into notes.

Soon Anne began to struggle to find words and add numbers. Her paintings grew increasingly symmetrical. Her final works, achieved when she was nearly mute, moved towards photographic realism.

“Painting was something she could do easily,” Adams said. “Every morning, she would come down and go into her office and paint,” eight hours a day.”

Tragically, the illness slowly claimed both Anne’s words and skills. But her drive to paint persisted.

“She got to the stage where she’d come down, sit down at her desk, with the paints in front of her,” said Robert Adams. “And she’d just look at them.”