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Glass half full

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They could be made to accept the most flagrant violations of reality, because they never fully grasped the enormity of what was demanded of them, and were not sufficiently interested in public events to notice what was happening.  By lack of understanding they remained sane.  They simply swallowed everything, and what they swallowed did them no harm, because it left no residue behind, just as a grain of corn will pass undigested through the body of a bird.

Orwell, 1984

In a letter to his mistress Louise Colet, the novelist Gustave Flaubert remarked that “to be stupid, and selfish, and to have good health are the three requirements for happiness.”  He then added, “though if stupidity is lacking, the others are useless.”

In all seriousness, a friend reminds me that, once all “this” is sort of over, one way of reconciling oneself to the fact that seventy-seven million people voted for Trump in 2024, after everything that had happened over the previous eight years, is that a very large percentage of those people are idiots, and consequently have never achieved the level of mens rea, as lawyers would say, to merit the consignment to a fiery pit that a more knowledgeable choice would require.

The post Glass half full appeared first on Lawyers, Guns & Money.

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VC isn’t VC anymore — understanding the rise of Cancer Capital

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We really, really need to talk about venture capital. Because it’s not “venture capital” anymore.

There’s a huge disconnect between what most people think of VC, where an investor has a big fund and cuts checks to help a founder build a company, and the current reality, where a handful of billionaire extremists use the cover of “VC” to advance an outrageous agenda where they’re accountable to no one.

I’m gonna explain this from a standpoint that almost never gets articulated: I’ve personally raised tens of millions of dollars in venture capital funding as CEO of startups, and been directly involved as a board member or advisor in raising hundreds of millions more. I’ve sat in board rooms, across the table from the people I’m talking about here, or been at the industry events that they frequent. So this isn’t sour grapes because these VCs wouldn’t cut me a check, or some chip on my shoulder about these investors due to a business deal. This is what I know about these bad actors because I’m part of the community of creators and inventors who build the things that they used to invest in — back when they still cared about innovation.

Many of the trends in society and politics that people are most angry about, from data centers being forced down everyone’s throats, to all of our favorite apps and services being enshittified, to politicians being paid to ignore the will of the people, are all being supercharged by these cancer capitalists. They have warped the structure of venture capital into a form of oligarchy that answers to no market, no regulators, and no voters. So it’s worth understanding exactly how they did it.

How Venture Capital became Cancer Capital

I’ll be breaking these points down in further detail, but just to begin framing the concept, I’ll lay out the core idea here in some bullet points (so that you’re not tempted to run this whole thing through an LLM):

  • Venture capital was only supposed to be a tiny segment of the overall capital market, but it has expanded to become the primary form of funding that new companies consider — it was never the only way, and it didn’t used to be the default one
  • VC was meant to be a small percentage of overall investment because it represents the high-risk, high-reward part of a portfolio; to be healthy, most of a portfolio — or most of an economy — needs to focus on assets that are more stable and predictable. But a cancer grows from a cell that a body needs in small, healthy amounts, and that turns deadly when it grows without limit until it harms, or even kills, its host.
  • As regulations have gotten looser in recent years, a handful of venture capital firms have become “do everything” funds that combine private equity with their existing VC businesses, and expand to manage massive stockpiles of tens of billions of dollars
  • The 1% of VC firms that get this big stop being exposed to the risk in their own investments at all — when you collect 2% a year to manage $50 billion, that’s a billion dollars landing in your pocket annually whether any company you funded lives or dies. Those firms also stop legally even being venture capital firms, making them unaccountable to markets, founders, or the law — and that’s how they become “Cancer Capital”
  • Meanwhile, the 99% of “normal” VCs don’t have the power or funding of the Cancer Capital firms, but are forced to play on the field that those firms define, even if they don’t like the way they do business
  • Since the Cancer Capital firms have become so powerful, the overall balance of power between founders and VCs has flipped; instead of founders having a company that VCs would try to fund, now VCs publish extremist political manifestos, and “founders” are just the people who are selected to carry out parts of those plans
  • The rest of the world doesn’t know: New founders and workers entering the tech industry are unaware that Cancer Capital has taken over, so many are still trying to play by the old rules, and can’t figure out why their ideas are being pushed into serving the goals of the Cancer Capital firms
  • Politicians and media still look at VC as if it works like it did 10 or 20 years ago, and cheer them on like they’re funding job creation or enabling new companies to grow, when their primary goal is concentrating power and wealth into the hands of the Cancer Capital tycoons. They keep getting fooled by this, over and over.
  • These days, venture firms are increasingly getting their funds from pension funds and retail retirement accounts, meaning the public (you!) are increasingly holding the bag for the parts of their portfolios that actually have some risk, even if you never intentionally made that choice
  • The shift away from IPOs in the tech industry has also encouraged these Cancer Capital firms to find ways to cash out long before companies ever go public, meaning they can make a massive return off of companies that never make a penny of profit, even if regular investors get screwed by the stock of a company once it actually gets listed on the public stock market.
  • Part of why this has gotten so corrupt is the way the Cancer Capital firms have transformed themselves into their post-VC forms. Because they’re not legally VC firms anymore, they’re free to buy shares directly from founders, or hold unlimited amounts of publicly-traded stock — exactly what they couldn’t do as regular VCs. They can even sell their investment in a company as an asset to another one of their own funds, and then book the increase in value as a profit, all without the company ever having made a penny. Another racket: a company that’s raised a bunch of cash in a funding round can buy out its early investors if they’re one of these post-VCs, so they can get paid off even if their portfolio company has never made a penny in profits or revenues.

All of this self-dealing, and the way that they’re isolated from any accountability, has made these firms become more and more shameless in their behavior. Former Andreessen Horowitz partner John O’Farrell publicly called out the firm (a rarity — the company is notoriously vindictive towards those who it decides are disloyal) for what he called its “political infiltration” of AI policy. Marc Andreessen, Ben Horowitz and their firm have put $115.3 million into this midterm cycle — nearly double their $63 million in 2024, and more than any other billionaire donor in the country, even including Elon Musk. Molly White, whose Tech Influence Watch tracks this money against FEC filings, shows that a16z alone accounts for more than 20% of all political contributions from the entire cohort of crypto and AI companies it follows. And they’re funneling these funds to candidates in both parties. This is a huge escalation from the tentative baby steps that folks like Zuckerberg were making in the Obama era, working on benign issues like trying to help immigrants.

And of course, it gets a lot worse than just their lobbying. As I have frequently noted, Andreessen Horowitz hired a man as a partner at their firm despite his having no background or qualifications in tech, finance, or startups whatsoever. His only discernible qualification was that he had choked my unarmed neighbor Jordan Neely to death on a subway car.

This is how brazen, how toxic and destructive, we’ve allowed the industry formerly known as venture capital to become. We must understand that it is no longer a financial machine that is used to fund startups, but a political and social machine focused on dismantling democracy and civil society. And it’s time to act accordingly.

Up next: we’ll dive into the specifics of many of the points laid out above, to understand more about how we got here.

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Preach it!
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Man fined $1.8 million by DHS for living in the US undocumented | CNN

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Hector “Alessandro” Negrete got the phone call nine months after he moved to Guadalajara, Mexico, hoping for a fresh start without the onerous weight of uncertainty and fear he carried in Los Angeles.

“Hey, you have something that says, ‘invoice to border patrol,’” Negrete recalls his former roommate telling him around 8 p.m. that night as he was meal-prepping after the gym. He consulted with his lawyer, and his roommate tore the envelope open.

“Vecino, what is this?” his roommate asked, calling him “neighbor” in Spanish.

Inside was a seven-digit number. He owed the Department of Homeland Security $1.8 million, the paper read.

“What the hell?” Negrete said he first thought. Perplexed, he initially believed the letter was fraudulent. He got on a FaceTime call with his roommate to process the shock.

His second thought: “Oh my God, I’m gonna lose my money. I’m gonna lose my job.”

The letter sent to his old address where he still files US taxes said he must pay a $1,820,352 civil penalty for his failure to comply with a 2009 deportation order, according to a copy of the notice reviewed by CNN.

He was only 3 months old when he and his parents fled violence in their Mexican hometown and immigrated to California.

Negrete remained in the US for over 15 years after receiving a final deportation order, repeatedly trying to gain legal status but facing barriers, he said.

But after President Donald Trump returned to office in 2025, 43-year-old Negrete’s immigration enforcement fears and declining nonprofit work made his life in Los Angeles increasingly untenable.

“Being in a cage in LA … is not the dream that I had for my future,” Negrete told CNN.

Early last year, Negrete decided to leave. He crossed into Tijuana, Mexico, by car in September 2025, before flying to Guadalajara two days later, Negrete said.

“I really genuinely felt that once I left the US, I would be done,” Negrete said.

Negrete’s situation is not unique. He is one of more than 100,000 undocumented immigrants who have received fines from DHS from the beginning of the second Trump administration to mid-July – amounting to more than $84 billion, DHS told CNN Monday. DHS has collected more than $1.2 million as of July 16, the agency said.

DHS warns that those who have received a final order of removal may be fined $998 per day if they don’t self-deport, but the fines can be forgiven if they use the CBP Home app to leave, according to a July news release from the agency. Those who do will receive a free flight home and an “exit bonus of $2,600.”

“Our message is clear: illegal aliens in the country unlawfully should leave now or face consequences—including financial penalties,” DHS said in a statement to CNN.

Charles Moore, a senior attorney at legal nonprofit Public Justice – which is suing the federal government for the immigration fines – said DHS is imposing penalties on people who may be complying with immigration requirements or pursuing lawful routes to remain in the country.

“This administration is weaponizing these fines to terrorize families and to push immigrants out of the country,” Moore said.

The federal government has argued the fine program was authorized by statutes passed by Congress nearly 30 years ago and is lawful.

“Whether an alien remains in country to pursue other forms of immigration relief is not a defense under the statutes,” the government said in a January court filing.

DHS referred CNN to the Treasury and Justice departments when reached for additional information.

Negrete and his lawyers twice provided evidence that he was living in Mexico, but officials demanded additional documentation, he and his attorney Marissa Montes said. Now Negrete – who works remotely for a US-based international nonprofit fighting ageism – is worried the government could pursue his US income and is considering joining litigation challenging the fines.

Negrete, born in Mexico in 1982, settled with his family first in South Los Angeles and later grew up primarily on Los Angeles’ east side in Boyle Heights.

Negrete spent a month in Mexico when he was around 6 years old. During his return trip back to the US, a woman hired to bring him across the border held him for more than a week and demanded additional money from his family, Negrete said. He described being tied in a vehicle and confined at her home.

“By the second night, I stopped crying as much because, at that young age, I guess I was just like, well, this is my new life,” he said.

Negrete did not discover his immigration status until after graduating from high school, he recounted.

Negrete said he had been accepted to the University of California, Berkeley, but learned he did not have a Social Security number while applying for scholarships.

“I remember asking my mom, like, ‘Oh, where’s my Social?’ … It was just a huge shock of confusion.”

Unable to afford college, he began working to help support his mother.

“I worked hard my entire life up to that point, and I couldn’t do anything. I couldn’t go to college,” Negrete said. “I didn’t know how to feel angry because I didn’t know who to be angry at.”

Negrete says he repeatedly tried to obtain legal status: First through his father, who became a lawful permanent resident after marrying a US citizen. But that effort failed because his father had accidentally omitted him from an immigration form, he said. A DUI conviction in 2008 had prevented Negrete from initially applying for Deferred Action for Childhood Arrivals (DACA) in 2012, though his record was eventually expunged, Montes told CNN. He then started the DACA application process before new applications were halted by the Trump administration in 2017, he said.

At the time, undocumented status was discussed through “shame or secrecy,” he recalled.

Negrete later became open about his status and got involved in immigrant rights and social justice work. He was a neighborhood council member and described himself as a “Dreamer,” although Negrete never received DACA status.

“Learning to tell my story from a place of resilience over fear was something that I needed to practice,” Negrete said.

Negrete built a career in nonprofits and philanthropy and became an openly undocumented and queer community advocate.

Negrete first considered leaving the US during Trump’s first term but said he stayed after his mother was diagnosed with cancer in late 2017.

Then came the second Trump administration. Negrete had lost work and tried drawing on savings before concluding that remaining in the US was no longer financially sustainable. He didn’t want to spend four years hiding or continue living with uncertainty over detention and removal, he explained.

“It wasn’t even fear of being deported. It was more the in-between space,” he said.

He had already decided to leave the US when immigration operations and protests in Los Angeles intensified in June 2025. He spent much of that summer indoors, too scared to go to the gym or engage in his usual activities. Then, he began saying his goodbyes.

“I didn’t want to live in a cage,” he said.

Before leaving, Negrete played in a final softball tournament in Sacramento. The week before, he held a yard sale and going-away party where friends bought most of his belongings – like his scary movie memorabilia collection – as keepsakes.

He gave guests cards with the message: “A new home, different door, same key.”

Months before leaving, Negrete shared the same sentiment in a “love letter” on Substack.

“After over 40 years of living in Los Angeles, a city that shaped me, strengthened me, and loved me back, I’ve decided to repatriate politically back to Mexico,” he wrote. “But let me be absolutely clear: this is not goodbye to LA, but rather a rebirth for me, and hopefully for some of you too.”

Negrete stuffed one large suitcase with coats and professional clothes, along with a smaller bag with his dog’s things. He said he left Los Angeles on September 4, 2025, and drove about three and a half hours on Interstate 5. Accompanied by friends and his dog, Negrete crossed the border into Tijuana, he remembered.

On the way, Negrete and his friends stopped at a beach for a spiritual ceremony. They spent the rest of the drive talking, and one of his friends pleaded, “It’s not too late; we can turn back,” Negrete recounted.

Negrete said he tried to “keep it together,” but he broke down that night in Tijuana when his friends shared a heartfelt video they made him – whom they lovingly referred to as “Ale.” A photo slideshow played and friends shared farewell messages on camera saying they would miss “the glue to our group.”

The next day, he took a one-way flight to Guadalajara, Negrete said, feeling anxious as he traveled farther into Mexico.

“What am I doing leaving this very comfortable, uncomfortable place?” Negrete remembered thinking. His friends dropped him off “like I was in college.”

Negrete described the move as emotionally painful yet ultimately empowering.

But the culture shock kicked in swiftly: Although he was among the strongest Spanish speakers in his US social circle, he initially struggled with Guadalajara’s local dialect, he joked. Finding housing proved to be another hurdle. It took him around four months to obtain Mexican identification and a tax number.

“I really had to navigate everything from being a tourist,” Negrete said.

By January, his life had settled into a familiar rhythm: During the week, Negrete worked, went to the gym and walked his dog. He spent weekends hiking, visiting dog parks and exploring Guadalajara with a new group of friends.

He described having lingering anxiety around law enforcement: Seeing police initially triggered worry conditioned by his years living without status in the US, though later he had begun to feel safer in Mexico.

“I’m like, wait, I’m fine. I’m good,” he said.

But back in Los Angeles, the life he thought he had escaped nearly a year prior came back to haunt him: the massive fine.

Dated May 5, the fine cites the Immigration and Nationality Act Section 274D(a), which authorizes DHS to impose monetary penalties on any noncitizen who “willfully fails or refuses to depart from the United States” after a final order of removal.

The notice says “If immigration officials can verify your departure, and if you are otherwise eligible for the debt rescission program, the United States will rescind the debt listed above.”

Negrete’s lawyers responded twice, but DHS dismissed their appeal and requested more evidence, according to his attorney and a notice reviewed by CNN.

“There was ample proof that Alessandro self-deported,” Montes said. “We provided that proof to the government, and even then, they said it wasn’t sufficient.”

Negrete said his lawyers had immediately responded to the initial letter, barely meeting the 15-day deadline for an appeal.

The appeal was filed on May 20 and the government denied it on June 2, his lawyers said. A day later, the government sent another invoice with the penalty and gave Negrete 10 days to appeal through email. Negrete responded on June 12, providing additional evidence he lives in Mexico, to which DHS responded that he didn’t submit enough evidence.

The fact that Negrete drove into Tijuana rather than flying directly from Los Angeles complicated documentation of his exit, Montes said. His attorneys say they submitted evidence that he left the country: signed declarations from a friend and reporter, his lease agreement in Guadalajara, domestic plane tickets within Mexico, a news article documenting his move and his Mexican ID documents.

Now, his legal team is preparing another submission that will include a passport stamp from another country.

The department also asked him to record his departure through the CBP Home app, but Negrete said he has not done so yet because he is concerned about how that information might be used.

DHS had said in the July release that by using the CBP Home app, “illegal aliens earn forgiveness for any civil fines or penalties for failing to depart the country.”

In July, two US senators sent a letter to the administration demanding the fines be halted, saying it has “abused” its authorities under the Illegal Immigration Reform and Immigration Responsibility Act “in an attempt to frighten immigrants—many of whom are seeking a green card or who have maintained lawful presence in the United States for decades.”

A lawsuit challenging the DHS fines was filed last November in Massachusetts on behalf of two women, proceeding under the pseudonyms Maria L. and Nancy M.

The lead attorney, Moore, said regulatory changes adopted in June 2025 removed several protections for fine recipients, which DHS said would “make it easier and more efficient to fine illegal aliens.”

Recipients previously had 30 days to respond and could request an extension; now they have 15 business days, the rule says.

Immigrants also previously received a “notice of intention to fine,” but the current notice is described as a “notice of violation and order.” Extensions and in-person interviews are unavailable, and the appeals process for the penalties has been transferred from an appeals board to DHS, according to the rule. The revisions also removed the ability to ask DHS to rescind a penalty after a final decision is made, so a person who later becomes a lawful permanent resident may remain liable for the fine, Moore said. DHS, however, can reopen decisions at any time to reconsider and reduce or rescind fines, according to the rule.

The notices do not adequately explain what conduct allegedly violated the law and the size of the fines violates the Constitution’s prohibition against excessive fines, the lawsuit in Massachusetts alleges.

Moore argues the fines are being used to financially and psychologically pressure immigrants to leave the US and the government is not adequately considering whether a person “willfully” failed to depart, as required by law.

The federal government has noted officials still make an individual determination of whether a person’s conduct was willful or voluntary, according to the January court filing.

CNN has reached out to the Department of Justice for comment.

A fine of $1.8 million appears to be among the most common penalty amounts, representing $998 a day over five years, Moore said.

About 70% of surveyed attorneys of $998-per-day fine recipients say their clients had obtained or were pursuing lawful status, according to an August report from the New York University School of Law’s Immigrant Rights Clinic. Like Negrete, over half had resided in the US for at least a decade after receiving their final deportation order.

Moore said the court held a hearing July 22 on the plaintiffs’ request for a stay, which would prevent the government from imposing or enforcing the fines in the challenged manner while litigation proceeds. The judge is now considering that motion, and a ruling is expected in the coming weeks or months, Moore said.

Because Negrete works for US clients and pays US taxes using an Individual Taxpayer Identification Number, he worries authorities could garnish his wages or take other collection measures, he said.

The government has filed over 50 lawsuits against fine recipients as of May, according to the NYU report. If successful, they could then garnish their wages, place a lien on their property or freeze funds in their bank accounts, the report states. By law and regulation, the federal government can also utilize administrative wage garnishment without a ruling in a collections suit, the report states.

The fines primarily affect working-class people who could never afford to pay the fine, the report said.

Montes said it remains unclear how the government intends to collect the penalties or whether it could garnish Negrete’s US-sourced wages.

Negrete is now saving more money and paying his rent in advance to ensure he has housing if the dispute interrupts his income.

He does not plan to move back to the US, but he does hope to eventually visit loved ones after a 10-year reentry bar expires, he said. His mother lives in Denver, and his father and most of his siblings are in Pomona, California. Because his parents have legal status and his siblings are US citizens, they can visit him instead.

Though he does not regret leaving, Negrete said getting legal advice might have changed how he approached his departure. After moving, Negrete’s lawyers told him his childhood trafficking experience might have provided a route to lawful status.

“I still believe that I made the best decision that I thought for myself in the moment,” Negrete said.

He said moving to Mexico has allowed him to travel and consider buying property – possibilities he could not imagine in Los Angeles.

But Negrete and Montes strongly urge undocumented people considering departure from the US to consult an immigration attorney first, investigate all potential relief and understand the consequences of leaving.

His advice to others: “Talk to a lawyer…Definitely don’t do it the way that I did.”

There are countless things Negrete says he misses about LA: his “chosen family,” playing with his softball team, running with the Boyle Heights Bridge Runners on Wednesdays and downtown nightlife on weekends.

“But I don’t miss living under persecution,” he said.

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Bad restaurant food

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Were 19th century European visitors to the United States inclined to be super critical about the food they ate in restaurants and hotels? It’s hard to know the answer, but they were often negative. An example was a woman from Scotland who grew so used to bad food that she was surprised to find a good breakfast in La Junta, Colorado, in the 1880s. She bonded with the proprietor, a German who had been trained in Paris, agreeing that Americans were mainly interested in quantity, not quality. [Note: old images were impossible to find, so I have used a variety of some I have collected over time, all from the latter 20th century.]

Delmonico’s in New York was, of course, a glowing exception. Outside of New York, however, the Delmonico name lost its majesty. A typical example was the Delmonico restaurant in Walla Walla WA. The local newspaper advised the new owner to change the name, noting that it had been eagerly adopted “by so many inferior restaurants and hotels about the country.”

Most Boston restaurants were judged bad. A Boston paper declared in the 1890s that “in no city of the same size are there such inferior restaurants, so little tavern life, and so little appreciation of good cookery . . .”

Widespread criticism continued into the 20th century when keeping fresh food in cold storage for extended periods was targeted as a major culprit, added to the fact that Americans didn’t know how to order in a restaurant and bolted down their food.

In a 1920s essay, food writer Elizabeth Robins Pennell viewed cafeterias and the automats as proof that Americans cared little for food. The automat was perfect for those who didn’t want to waste time eating, she declared, “since after you put your money in the slot, the sandwich or salad, the coffee or chocolate that comes out may be swallowed as you stand – not one fraction of a second lost in a hunt for a seat.” She judged that “The man who first wrote ‘Eats’ above his restaurant door spoke the truth better than he knew, in one word pointing out to us the depths to which we have sunk.”

Duncan Hines criticized the nation’s restaurant mercilessly in the 1940s. He felt it was more dangerous to eat your way across the country than to drive across it. He admitted that he “would like to be food dictator of the U.S.A. just long enough to padlock two thirds of the places that call themselves cafes or restaurants.” He was expressing a common view of the food available to highway travelers, as also expressed in a 1951 Life magazine article which concluded that “In whatever region he is traveling, the American tourist soon finds that good simple American cooking is an elusive myth.”

But it wasn’t as though the dining public was necessarily going to fare better in cities. Occasionally restaurant reviewers revealed how unenthusiastic they were about a restaurant, without exactly trashing it. In a review a San Antonio oyster restaurant’s food, decor, and service were branded in turn as okay, inoffensive, and not exciting or depressing. The conclusion was that “You can pay a lot more for a lot less, and that’s the most exciting news of this review.”

In 1968 a columnist summed up restaurants of that time by agreeing with an experienced professional that mediocre restaurant food had become the norm. As examples he mentioned ‘The drive-in eatery, the Ma-and-Pa hash-house, the roadside ‘Stop-and-Eat’ wagon, the Main Street ‘Greasy Spoon.’ Hamburger. Ham-and-eggs. Canned fruit salad. Buns and coffee, and suggested diners might as well just “Take what they put before you. Slather it with ketchup. Eat and hurry on.’

By the 1980s, chain restaurants had become omnipresent across the nation. Two Chicago Tribune critics ranked 15 chains. They agreed that overall the quality of food in them was “mediocre.” The bottom five, which included the Ground Round (fatty, flavorless, and overcooked beef), Howard Johnson’s (rubbery clams, over-breaded shrimp, too much fried food), the International House of Pancakes (nothing-special crepes, old toppings, tough steak, plain lettuce salads), Shakey’s (substandard pizza, starchy buffet), and Wag’s (withered salad greens, chili tasting like canned), came in for heavy criticism.

However much patrons might complain about food (or service) in a restaurant, they tended to make their peace and accept less than perfection at restaurants that they frequently patronized. They kept their criticisms to themselves – even though restaurateurs say they would have preferred to hear them.

In 1993 columnist Kevin Cowherd described a fantasy eruption of anger that might occur after taking a bite of bad food in a restaurant: “. . . it’s so awful that you spit the food into your hand and fling it angrily at the ceiling and then stand up, backhand all the silverware and glasses off your table and scream . . .” He admits he never threw a fit like this but says, “Just once I want to react to lousy restaurant food with a major, king-hell tantrum that shakes the walls and peels the paint and makes everyone around me cringe.”

Whew!

© Jan Whitaker, 2026



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“An example was a woman from Scotland who grew so used to bad food that she was surprised to find a good breakfast in La Junta, Colorado, in the 1880s. She bonded with the proprietor, a German who had been trained in Paris, agreeing that Americans were mainly interested in quantity, not quality.”
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When do infections lead to long COVID? Scientists close in on triggers and treatments for post-viral syndromes

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In 2004, Amy Proal got an infection that changed her life. “I was in my pre-med, last year of college, and totally tanked,” she says. “No one could tell me what it was, everybody said my blood work was fine — sent to a psychiatrist, the usual story.” She started reading papers from her sickbed and soon realized that she wasn’t the only one with unexplained symptoms that lingered after an infection.

A year later, she was diagnosed with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). She managed to improve her symptoms with antivirals and other drugs, and went on to do a PhD in microbiology, studying the lasting consequences of pathogens. In 2018, she co-founded PolyBio, a foundation in Medford, Massachusetts, that advances research on infection-associated chronic illnesses. “Then,” Proal says, “COVID hit.”

COVID-19 killed millions of people, and left millions of others with lingering health problems caused by the SARS-CoV-2 virus. The chronic condition became known as long COVID. A 2024 study estimated that 400 million people around the world have long COVID1, with an annual economic burden of around US$1 trillion.

What causes long COVID? Case builds for rogue antibodies

The condition’s existence prompted a surge of interest in post-acute infection syndromes. Over the past six years, thousands of studies have explored the mechanisms underlying long COVID, its similarities to other post-infection conditions and potential treatments. In December 2020, the US government allocated $1.15 billion to study the chronic consequences of SARS-CoV-2 and, last year, Germany announced €500 million ($580 million) in funding for research into post-infectious diseases. “The COVID pandemic has shone a light on this family of post-acute infection conditions,” says David Putrino, a neuroscientist at Icahn School of Medicine at Mount Sinai in New York City.

Nonetheless, the conditions’ health and financial burden still strongly outweighs the funding. “It’s not a priority, despite having a major destructive influence on our society,” says Chris Ponting, a geneticist at the University of Edinburgh, UK.

The community is working to understand the basic biology underlying these conditions and find reliable disease markers, the lack of which is the main obstacle to developing treatments. How acute infections trigger chronic illnesses remains unclear, but many researchers think the field is closing in on explanations. “We certainly don’t have the answer,” says Michael Peluso, an infectious-disease clinician at the University of California, San Francisco. “But we have a lot of leads.”

Chronic shadows

In 1894, a few years after an epidemic of respiratory disease swept the world, English physician Thomas Dowse described a cluster of symptoms that lingered long after infection. He called the condition ‘post-influenza exhaustion’. Numerous other chronic illnesses, including post-polio syndrome, post-Ebola syndrome and post-treatment Lyme disease syndrome, have since been linked to pathogens. Symptoms vary, but fatigue and neurological features are common. “Almost every infection, viral, bacterial, parasite, is associated with chronic symptoms where a subset of people don’t recover,” Proal says.

Can long COVID be prevented? Two drugs finally show promise

These people were often dismissed by physicians, but the COVID-19 pandemic forced the world to take notice. Data collected in 2023–24 by the US Centers for Disease Control and Prevention (CDC) suggested that around 6% of adults have long COVID (see go.nature.com/4zbjmmh).

In February 2021, the US National Institutes of Health (NIH) launched the RECOVER initiative. The programme focused mainly on assembling large cohorts of people with long COVID, characterizing their symptoms and collecting samples. It has been criticized on a few grounds — for not testing enough treatments, for example — but some researchers say that the large-scale infrastructure the initiative built will pay off in the long term.

Scientists interested in post-infection disorders are joining forces. “Many collaborations are happening, starting from long-COVID researchers reaching out to people who’ve been doing ME/CFS research for decades,” says Akiko Iwasaki, an immunobiologist at Yale School of Medicine in New Haven, Connecticut. Iwasaki and Danny Altmann, an immunologist at Imperial College London, helped to organize a symposium in Santa Fe, New Mexico, in August 2025, bringing together specialists in many different post-infection syndromes. “All the talk was about shared pathways and mechanisms,” Altmann says.

The existence of long COVID gave other disorders like it more credibility, helping to dispel the idea that these conditions were psychological. This narrative has dogged people with ME/CFS for decades, but the CDC and the UK National Institute for Health and Care Excellence both now define the condition as a biological illness. Symptoms of ME/CFS include fatigue, cognitive impairment and — a hallmark feature — post-exertional malaise, the worsening of symptoms after physical or mental exertion.

There is a lot of overlap between the various post-infection syndromes and many also have subtypes. Some people with long COVID, for example, have cardiovascular issues, others have severe brain fog and another subset has symptoms associated with an ME/CFS diagnosis. An important difference between long COVID and ME/CFS is that the former is defined by its trigger and the latter by its symptoms regardless of cause (although reports of previous infection are common).

In fact, most post-infection syndromes leave a proportion of people with symptoms that meet ME/CFS criteria. “There’s nothing unusual about SARS-CoV-2 as a trigger,” Ponting says.

Disease drivers

The emerging picture is of overlapping mechanisms and symptoms shared by many such syndromes. “It’s important for us to consider these diseases together,” Iwasaki says.

Researchers have made progress uncovering some important players, including the immune system. Evidence points to dysregulated immune cells, chronic low-level inflammation and autoantibodies — immune cells that attack the body’s own tissues. Scientists focusing on long COVID have found that SARS-CoV-2 persists in some form2. It can also reactivate other dormant viruses3, in particular those in the herpesvirus family.

Long-COVID signatures identified in huge analysis of blood proteins

Studies have also shown that small blood vessels and the endothelial cells that line them are damaged4. The autonomic nervous system, which regulates heart rate and breathing, is frequently affected and the gut microbiota altered. Mitochondria, the cell’s power plants, are often damaged; this could contribute to symptoms of fatigue.

These mechanisms are probably intertwined. For example, “many viruses infect the gut and lead to long-lasting low-level immune activation”, which in turn disturbs the gut microbiota, says Carmen Scheibenbogen, an immunologist at Charité University Medicine Berlin. When the autonomic nervous system is affected, poorly regulated heart rate and blood pressure impair blood flow, which in turn could starve mitochondria, disrupting energy production and damaging tissues, Scheibenbogen says. “So, what would happen to us if we ran a marathon happens to ME patients from climbing two stairs.”

The relative importance of various mechanisms could provide a way to group people into subsets: those with autoantibodies, say, or signs of viral persistence. This means that it’s unlikely that any one treatment will benefit everybody, although some might work for several diseases.

Strong leads

Among the many mechanisms that could drive pathology, some are seen as stronger candidates than others. Researchers are focusing in particular on immune dysfunction — including autoantibodies — and viral persistence. “The spotlight is on those two areas,” Altmann says.

Autoantibodies are a defining feature of autoimmune diseases, which are more common in women than in men, as are long COVID and ME/CFS. One explanation for how these autoantibodies develop is that the immune system mistakes viral proteins for similar human ones and attacks both.

Several groups have shown that antibodies from people with long COVID make mice ill, providing what many consider the strongest evidence so far that autoimmunity causes symptoms. In a study published in May, an antibody called immunoglobulin G (IgG) taken from people with long COVID conferred hypersensitivity to pain when injected into mice5.

Scheibenbogen’s group has tried filtering autoantibodies from the blood using a procedure called immunoadsorption. The researchers recruited people diagnosed with ME/CFS after having COVID-19. The procedure reduced both autoantibody levels and symptom severity in most people6. There was no placebo group, so firm conclusions can’t be drawn. Moreover, immunoadsorption is too complex to scale up to large numbers of people, so the team is planning to do placebo-controlled trials of drugs that deplete antibody-producing cells called B cells and plasmablasts.

A team in Norway has already done a small study using this strategy, with promising results. Øystein Fluge, a physician at the University of Bergen, and his colleagues treated ten people with ME/CFS with daratumumab, an antibody that targets plasmablasts. They saw strong benefits in some participants that remained for up to two years7. Those who responded also had larger drops in immunoglobulin levels midway through the trial than did those who did not. A larger, placebo-controlled trial of daratumumab, called ResetME, launched in June 2025 and results are expected between 2028 and 2030.

Meanwhile, numerous trials are targeting long-COVID symptoms by trying to clear lingering viral particles or fragments. Mounting evidence indicates that the virus can hang around for years and this has led some researchers to change their views on the basic biology of infection. “I wasn’t a believer in viral persistence when I started in this field,” says Peluso. “But if nothing else, we have fundamentally started to rework how we think about pathogens that should be transient.”

It’s not clear whether viruses persist as genetic fragments or as whole particles in organs such as the brain and eyes, which are partially separated from the immune system. But something seems to remain. A 2024 study found that participants who had long COVID after a SARS-CoV-2 infection were more than twice as likely to have viral proteins in their blood as were people who recovered — up to 14 months after infection8.

Long-COVID research just got a big funding boost: will it find new treatments?

If viral persistence is causing symptoms, then antivirals could improve things. But evidence for this is inconclusive. A trial run by RECOVER tested paxlovid, a SARS-CoV-2 antiviral, but preliminary analyses failed to find a benefit. The trial’s design could have contributed, says Proal: evidence of viral persistence wasn’t required for enrolment, for instance, and the 25-day treatment was too short.

Many researchers advocate for smaller, faster trials, which are not designed to produce clinically significant results, so much as to help scientists quickly test theories and move promising therapies into larger trials. They call this approach “experimental medicine”.

Inspiration often comes from people who have been thinking about these conditions for a long time, says Putrino. One such individual, William Pridgen, a physician in Tuscaloosa, Alabama, has for years been offering people with ME/CFS and fibromyalgia (a condition characterized by muscle pain and fatigue) a combination of herpes antivirals. The theory is that an infection or other source of stress could reactivate dormant herpesviruses, causing a chronic syndrome.

One of his formulations, a combination of two antivirals, is entering phase III trials for fibromyalgia. Pridgen is also testing a trio of drugs — a pair of herpes antivirals plus paxlovid — that simultaneously targets SARS-CoV-2 persistence and herpesvirus reactivation. He and Putrino published a study in January testing this cocktail in 24 people with long COVID9. Half took only the antiviral pair for 120 days; the rest received paxlovid as well. Everybody’s symptoms improved, but the 12 participants who received the three drugs did much better than did those who received two, and the improvements were still seen after two years. In January, the US Food and Drug Administration granted the researchers an Investigational New Drug exemption to run a larger, placebo-controlled trial of the drug trio.

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Scientists uncover shared biology behind profound fatigue in five major illnesses | EurekAlert!

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A shared biological secret that helps explain chronic exhaustion in conditions including long Covid and PTSD has been discovered by researchers at the University of East Anglia and Oxford BioDynamics.

A new paper published today in the Journal of Translational Medicine reveals striking biological similarities between five major illnesses which until now have largely been viewed as separate disorders.

The findings suggest that chronic fatigue syndrome (also known as ME), long Covid, post-traumatic stress disorder (PTSD), rheumatoid arthritis and multiple sclerosis (MS) may be driven by common underlying mechanisms.

This is despite the conditions being triggered by different events - ranging from viral infections to psychological trauma or autoimmune responses.

Lead researcher Prof Dmitry Pshezhetskiy, from UEA’s Norwich Medical School, said: “Until now, illnesses including long Covid, PTSD, ME/CFS, multiple sclerosis and rheumatoid arthritis were viewed as seemingly unrelated and triggered by completely different events.

“ME/CFS often follows viral infection. Long Covid develops after SARS-CoV-2 infection. PTSD emerges after traumatic experiences. Rheumatoid arthritis is an autoimmune disease attacking the joints, while multiple sclerosis attacks the nervous system.

“But one thing that links them all is that patients frequently report remarkably similar symptoms - overwhelming fatigue, brain fog, poor concentration, disturbed sleep, autonomic dysfunction and a dramatic reduction in everyday functioning.

“We wanted to find out why this is.

“What we discovered is something approaching a biological unifying theory of fatigue.”

How the research happened

Rather than conventionally analysing DNA sequences, researchers from UEA used Oxford BioDynamics' innovative EpiSwitch® Orion platform, which examines the three-dimensional architecture of the genome, essentially studying how DNA folds and interacts inside living cells.

The analysis was computational. Published genomic data for long Covid, PTSD, rheumatoid arthritis and multiple sclerosis, drawn from existing genome-wide association studies, were combined with 3D genomic data from an earlier ME/CFS patient study, without needing to collect new patient samples.

“DNA is folded in our cells, so regions far apart in the linear sequence can touch, and those contact points are where genes get controlled. Orion predicts where these contact points are likely to be,” said Dr Ewan Hunter, Chief Data Officer at Oxford BioDynamics.

Applied to the five conditions, Orion found that genetic changes, that appeared to have little in common, connected into the same regulatory circuitry.

Prof Pshezhetskiy said: “We expected to find at least some overlap in genes across the conditions. But we actually found the opposite.

“At an individual gene level, there was surprisingly little direct overlap between ong Covid, ME/CFS, PTSD, multiple sclerosis and rheumatoid arthritis.

“But when we analysed how those genes interact in complex biological networks, a completely different picture emerged. Suddenly, the diseases appeared deeply connected.

“This is not something you can see by reading the genetic sequence alone, which is why these conditions may have looked unrelated for so long.

“Although these conditions are triggered by completely different events, they may ultimately disrupt the same fundamental biological systems and produce the similarly devastating exhaustion experienced by millions worldwide.”

The study found that genes linked to each illness were feeding into the same major biological systems - including immune and inflammatory signalling, mitochondrial energy production, metabolic regulation, stress-response mechanisms and neuroendocrine signalling.

Why trauma and viruses can produce the same symptoms

The team say the study could help explain why people who have experienced a viral infection or psychological trauma can go on to develop similar symptoms.

“We now think the answer may lie in shared regulatory networks embedded within the body's immune and metabolic systems,” said Prof Pshezhetskiy.

“A Covid infection may trigger prolonged immune activation. Traumatic stress may disrupt stress-hormone pathways and inflammatory responses.

“But both disturbances appear capable of converging on common biological circuits controlling energy production, immune regulation and cellular resilience.

“When those systems become persistently dysregulated, the result may be the profound and disabling fatigue seen across multiple disorders.”

A new role for the immune system

The study also highlighted several ‘hub genes’ that sit at the busiest points within these shared networks.

Among them were genes involved in immune regulation, inflammatory signalling and mitochondrial energy production. The authors stress that these are candidates identified by the analysis, and more work is needed to confirm what role they play.

One part of the analysis, looking specifically at ME/CFS, flagged LAG3 as a gene to investigate. This is a molecule associated with ‘T-cell exhaustion’, a state in which immune cells become worn out after prolonged activation.

The team say that if this can be confirmed in further studies, it could help explain why many patients appear stuck in a state of chronic illness long after the original trigger has disappeared.

“This work adds to a growing body of evidence suggesting that persistent immune dysfunction may play a far larger role in chronic fatigue-related illnesses than previously recognised,” said Prof Pshezhetskiy.

Paving the way for blood tests and treatments

“Perhaps the most significant implication is what this could mean for diagnosis.

“ME/CFS and long Covid are currently diagnosed largely through symptoms, with no universally accepted laboratory test available.

“That has left many patients facing years of uncertainty.”

Separate earlier work using the EpiSwitch platform had already produced a blood-based ME/CFS test promising high levels of diagnostic accuracy, ready to be taken through further validation needed for clinical use.

The new findings raise the prospect of signatures shared across several conditions, beyond only ME/CFS.

“We hope our work could pave the way for objective blood tests capable of identifying underlying biological signatures rather than relying solely on patient-reported symptoms,” said Prof Pshezhetskiy.

Now, the team hope the newly identified shared biological pathways could eventually lead to broader diagnostic tools and even treatments that work across several chronic conditions.

“Rather than viewing long Covid, ME/CFS, PTSD, rheumatoid arthritis and multiple sclerosis as entirely separate disorders, we now think they may be different manifestations of disturbed biological networks operating throughout the body.

“In that scenario, chronic exhaustion is not simply a symptom. It is the visible consequence of a deeper systems failure affecting immune function, metabolism and stress-response pathways.

“This study offers a framework for understanding how different triggers can converge to cause the exact same profound clinical exhaustion.”

This research was led by the University of East Anglia in collaboration with Oxford BioDynamics, the London School of Hygiene and Tropical Medicine, and Cornwall Partnership NHS Foundation Trust.

‘Beyond Genes: EpiSwitch® and Orion Platform-powered 3D Genome Architecture Biomarkers Reveal Shared Biology Across ME/CFS, Long COVID, PTSD, Rheumatoid Arthritis, and Multiple Sclerosis’ is published in the Journal of Translational Medicine.

ENDS


Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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