Pharmaceutical Freedom: Why Patients Have a Right to Self-Medicate

If Patients Can Refuse Care, Why Can't They Access It?
A Psychiatrist’s Read of Jessica Flanigan's "Pharmaceutical Freedom"

V. The Third Person in the Room

The clinical encounter is not a two-party relationship. There is a third presence in the room, composed of malpractice precedent, DEA scrutiny, prior-authorization architecture, board-of-medicine expectations, and institutional risk management. It does not speak. It shapes what can be offered, what can be discussed openly, and what stays outside the bounds of the conversation. The patient senses it. The prescriber feels it more acutely.

Flanigan directs her critique at the state, as if the state were a discrete actor whose policies could be evaluated on their merits and replaced with better ones. The state is not in the room. Individual prescribers are in the room, and the policies of the state arrive there refracted through professional liability, employer policy, payer requirements, and the residue of every malpractice case any of us has read about. What looks like medical paternalism is, in many cases, professional survival adapting to a system in which the visible costs of one kind of error are concentrated and the visible costs of the other are dispersed.

The cost of error is asymmetrically distributed. A patient who refuses care and deteriorates is generally respected as having exercised autonomy; the death is sad, but it is hers. A prescriber who provides risky access and watches harm follow is scrutinized, second-guessed, sometimes sued, occasionally disciplined by their state medical board. These outcomes are not philosophically symmetric, and prescribers have absorbed that asymmetry into their reflexes. Daniel Carpenter, in his analysis of the FDA in Reputation and Power, names the same pattern at the regulatory scale: visible harms are minimized, dispersed harms are tolerated, and the institution's incentive structure runs in one direction. The clinic operates on the same logic as the agency, scaled to a single examination room.

There is something genuinely appealing to me about Flanigan's proposal from inside this structure. If physicians are not the gatekeepers, they are not the bearers of the consequences. The consultant role, in which I inform rather than authorize, is the more honest description of what I am actually competent to do. It removes a distortion in the encounter that the current regulatory structure quietly imposes. I would, in some moods, sign on tomorrow.

The cost of removing it is that gatekeeping organizes responsibility in ways that are not always coercive. The patient who can be conditionally offered a risky medication, contingent on a safety plan and a follow-up visit, is in a different conversation than the patient who can simply buy it at retail. Whether that difference is therapeutic or merely bureaucratic depends on the case, the patient, and the medication; the honest answer is that it is both, in proportions that vary.

Quong's distinction returns here in a form Flanigan does not fully address. Removing physician gatekeeping does not eliminate the coercive structure around pharmaceutical decisions. It relocates it. Insurers, employers, licensing bodies, fitness-for-duty examiners, family courts, child-welfare agencies: these are the secondary gatekeepers waiting to absorb the function. A pilot whose airline learns he has been self-medicating does not become more autonomous because his prescriber is no longer the bottleneck. Flanigan's payment proposals, which include collective insurance bargaining, conditional reimbursement, and vouchers, are sensible on their own terms, but they describe a system in which insurers retain decisive control over which drugs are practically affordable, and that control is itself a form of gatekeeping.

Her reform of the prescription system would not abolish gatekeeping. It would migrate it from a clinical relationship, where there is at least some individual accountability and some possibility of negotiation, into administrative structures with less of either.

VI. What the Book Gets Uncomfortably Right

This is where Flanigan's abstraction becomes clinically useful. There is a version of her argument that sounds exaggerated until you follow it through the structure described above. Delay accumulates in individual patients. In aggregate it looks like a policy. In the clinic it looks like a pattern.

Four things in the book survive clinical scrutiny better than I would like them to.

The first is that delay is a body count, and the count is not zero. Flanigan's most provocative line, the one about prescription requirements killing people, lands harder here than in the section that introduced it, because by now the reader has the structure to see what she means. The sequence is familiar to anyone who has watched a patient cycle through the standard-of-care options for a treatment-resistant condition. An early-phase signal is not strong enough to meet the chosen endpoint. The endpoint was chosen to withstand regulatory scrutiny rather than to register clinical benefit. The trial extends. Approval waits. The patient cycles through partial responses, accumulates side effects, loses jobs and relationships, and eventually either stabilizes on something inadequate or does not stabilize at all. The drug arrives later, with narrower labeling and higher evidentiary confidence. Some patients benefit. Others have already moved on, in one direction or another. No one counts the ones who did not wait.

This is the asymmetry Carpenter describes at institutional scale. The cost of being wrong in one direction is concentrated, identifiable, traceable to a decision; the cost of being wrong in the other direction is dispersed across a population that never appears in the same frame as the decision that produced it. That asymmetry constrains what I can offer the person sitting in front of me. The menu of available treatments at any given visit is a function of what is approved, what is labeled, what is defensible, and what is reimbursable. I am choosing among the survivors of a filtration process that selected for evidentiary confidence at the cost of timeliness, and for legal defensibility at the cost of clinical range. Flanigan is right that delay carries a cost. Carpenter explains why that cost is tolerated. The clinic is where the two positions meet and refuse to resolve.

The second is regulatory inconsistency. Alcohol is sold at gas stations. Tobacco is regulated at point of sale rather than at access. The supplement industry sells substances with measurable pharmacological effects under almost no oversight, some of which overlap meaningfully with prescription pharmacology. Meanwhile, drugs with established mechanisms, known dosing, decades of safety data, and clear therapeutic niches remain tightly controlled. The boundary does not track risk. It tracks regulatory history, which is to say it tracks the order in which different industries developed, captured their respective agencies, and stabilized their privileges.

The third is that restriction redistributes harm rather than eliminating it, and the redistribution is stratified by resources. The patients who already operate in a world of pharmaceutical freedom are overwhelmingly wealthy, educated, well-connected, and white. They have the time, language, money, and confidence to use international pharmacies, online vendors, supplement markets, ketamine-clinic networks, and direct-to-consumer telehealth. They self-experiment with peptides, pay cash for novel neuromodulation protocols, and design off-label regimens with help from physicians willing to advise them and from AI tools that explain pharmacokinetics on demand. One patient with bipolar disorder, able to afford a nonstandard neuromodulation course out of pocket, designed a variant protocol after reading the literature; it seems to have helped him, and the clinical work was free to proceed because he could bypass the insurance pathway entirely. Another patient, after years of severe fibromyalgia, researched a newly approved neurosteroid obsessively and had two weeks of striking relief on samples left at an office; her right-to-try appeal failed and she could not afford the cash price. What separated those two patients was resources rather than biology. Patients without those resources remain inside the formal system, where access is slower, narrower, and subject to authorization workflows designed by people who do not have to use them. Psychedelic therapy is the cleanest contemporary example: psilocybin retreats in legal jurisdictions, ketamine clinics, and underground guides are available to people who can afford them, while the same compounds remain federally inaccessible to the patients most likely to benefit and least likely to find a way around the prohibition.

The fourth is that restriction shapes honesty. This is essentially Anomaly's learned-helplessness point, and it deserves the most attention. When access depends on prescriber approval, the patient has a strong incentive to present in whatever way maximizes the likelihood of getting what they want. Symptoms are emphasized or hidden. Histories are edited. Substance use gets reframed as something else, or omitted. This is not lying in the sense that anyone would prosecute. It is adaptation to a system where the prescriber's authority over access creates a corresponding pressure on the information that prescribers receive. Anomaly's framing draws on Mill: state restrictions, by promising to manage risks on the citizen's behalf, can permanently stunt the development of the very faculties that would have allowed the citizen to manage them. The clinical version is more local. The frame that promises to protect the patient from bad decisions also produces the patient who cannot tell his doctor what he is actually doing.

A system that restricts access does not eliminate risk. It redistributes it: toward patients who cannot find their way around the workarounds, into clinical encounters where honesty has been priced out, and onto the timelines of patients waiting for permission that may never arrive. The conversation in which the options run out happens more often than the policy debate suggests.

VII. Toward a Capacity-Based Hybrid

The book's great virtue is that it forces clinicians to defend the gatekeeping role rather than assume it. Most pharmaceutical regulation is implicitly risk-based. The higher the perceived risk of a drug, the tighter the controls on access. Flanigan's most useful contribution, after the symmetry argument, is to demonstrate that risk on its own is a poor foundation for coercion; many activities of comparable or greater risk go entirely unrestricted, and the threshold at which paternalism becomes legitimate is not derived from any consistent principle.

A capacity-based framework offers a different organizing principle. The threshold for restricting access is not the level of risk involved, but the integrity of the decision-making process about that risk. [...]

The right analogy is not the prescriber as gatekeeper but the prescriber as fiduciary advisor. Financial advisors do not authorize their clients' trades; they cannot prevent a client from making a foolish investment. What they offer is a relationship across time, a track record of trust long enough to make persuasion possible, and the authority that comes from being someone the client has chosen to listen to. The advisor's job is to deepen the conditions under which the client can exercise autonomy well, not to override it. Having no coercive authority is what makes the advisor freer to be honest about what the client is doing wrong. That structural freedom is precisely what the prescriber's role currently lacks.

by Anonymous, Astral Codex Ten |  Read more:

[ed. From the 2026 ACT annual book review contest (here). This is a recurring frustration - patient requests for various drug prescriptions versus what doctors will actually prescribe (for a variety of reasons articulated in this review, none of them transparent). Since a patient generally has more intimate insight into how their body functions and feels than a physician does you'd think they'd have more influence in the decision-making process, but no. And it's hard to discern what's driving those decisions - see the list at the top of this post. (As an aside, I've never understood why there are so many drug commercials on nightly news, and who they're directed at. Do you know of anyone going to a doctor and saying "hey, I saw a new drug for my condition on tv last night, and how about we give it a try". Try it, see what kind of response you get.]

Seniors in Medicare to Get Obesity Drug Coverage

Millions of older Americans in Medicare are about to gain access to obesity drugs for the first time — but that landmark shift may be flying under the radar for many of them.

Starting Wednesday, eligible beneficiaries can get obesity drugs through Medicare’s new Bridge demonstration program for a monthly copay of just $50. The coverage marks a long-sought victory for patients, physicians and obesity advocates who have pushed for broader access to the blockbuster treatments from Novo Nordisk and Eli Lilly, which have remained out of reach for many Americans.

But a staggering 82% of all older Americans — including 79% of Republicans and 84% of Democrats — say they are unaware that Medicare is about to begin covering obesity drugs, according to a survey released in early June by the Obesity Care Advocacy Network. The survey, conducted in late March among more than 2,100 adults ages 65 and older, was completed weeks before the government announced it would extend the Bridge program through 2027.

That data may not come as a surprise: While the government has done robust outreach to healthcare providers and pharmacists, some physicians and other experts told CNBC that they have noticed limited advertising of the new coverage to the general public from the Centers for Medicare & Medicaid Services or Novo and Lilly.

There may be good reasons for it. CMS has done limited public outreach on the program ahead of July 1 because beneficiaries are “most moved to take action” when a benefit is actually available to them, an agency official told reporters on Thursday. They added that CMS will put out more promotions after the launch, “in the interest of being good stewards of our taxpayer dollars.”

Other experts also told CNBC that it may come down to making sure providers and pharmacies are prepared and resources are in place before pursuing broad public outreach. [...]

Unlike traditional Medicare drug coverage, enrollment in the Bridge program is not automatic. Patients must meet eligibility requirements, obtain a prescription and receive prior authorization approval through CMS before coverage begins.

by Annika Kim Constantino, CNBC | Read more:
Image: Dhiraj Singh|Bloomberg|Getty Images

[ed. Feels like there's more to this story. Why is no one clamoring to get credit (or market share)?]

Shane Mauss | Trips: Second Dose

Psychedelic experiences are famously hard to describe. So comedian Shane Mauss didn’t just describe them—he built a way to show them. 

In TRIPS: Second Dose, Shane dives into ayahuasca, DMT, and ketamine, translating hyperspace, out-of-body experiences, and cosmic rodeos into big laughs and bigger perspective. Filmed inside the 360° immersive madness of Meow Wolf Denver, the visuals are mixed and synced live by Michael Strauss, fusing 25 years of concert/festival visuals with work from 20+ visionary artists curated by Shane.

[ed. Pretty funny and great graphics. I've always wondered why more comedians haven't followed the Cheech and Chong formula from decades ago.]

Ben Sasse's Warning

When Ben Sasse walked onto the Senate floor in November 2015 to deliver his first speech as a member of the upper chamber, he did something unusual: He had waited a full year to speak. It’s part of a Senate tradition known as the “maiden speech.” A historian by training and a management consulting associate by early vocation, he had spent his first year in the chamber interviewing colleagues, studying how the institution functioned, and developing a diagnosis before offering it publicly. When he finally spoke, the speech landed with enough force that Sen. Mitch McConnell (R-KY) distributed the text to every Republican senator, a gesture the Senate GOP leader at the time rarely made.

“No one in this body thinks the Senate is laser-focused on the most pressing issues facing the nation,” Sasse told his colleagues. “No one.”

The indictment was bipartisan, surgical, and delivered with the calm of a man who had considered it carefully before speaking. The Senate, he argued, had surrendered its institutional identity to the rhythms of the 24-hour news cycle, to the demand for sound bites, and to the incentive to grandstand for a narrow base and raise money rather than legislate for a country. “The people despise us all,” he said. “And why is this? Because we’re not doing our job.”

It served as a warning that went unheeded, and 11 years later, we’re watching more dysfunction in government than ever before. Sasse, now dying of Stage 4 pancreatic cancer at 54, is still saying the same thing. The diagnosis has not changed the message. It has sharpened it.

Whether Sasse was a “good” or “effective” senator is debatable. Whether Washington currently has enough senators like him is not a close question.

The criticism that followed him throughout his eight-year tenure is almost entirely subjective. His critics on the Left saw a man willing to deplore Trumpism in public while voting with President Donald Trump‘s agenda in practice. His critics on the Right, particularly as the party realigned, saw a posturing institutionalist more interested in making points and serving as a pundit than in getting on board fully with the president’s policies. The most durable version of this critique runs something like: He gave great speeches and passed no significant legislation.

Yuval Levin, founding editor of National Affairs and director of Social, Cultural, and Constitutional Studies at the American Enterprise Institute, largely rejects both sets of criticisms. On the Trump question specifically, Levin is direct: “The notion that there was much more he could have done to hold Trump to account is misdirected and mistaken. He took on Trump when he disagreed with him, and when he thought Trump had exceeded his authority or violated his oath. And unlike most Senate Republican critics of Trump, he ran for reelection and won after doing that.”

The objection to the lack of signature legislation mistakes the Senate’s function for a body it was never designed to be. In the framework Sasse spent years articulating, the Senate is not primarily a factory for producing legislation. It is a deliberative institution meant to apply friction to democratic impulses in the House of Representatives, to slow things down when people want to move too fast, and to force the executive and judiciary to operate within appropriate constitutional limits. By that standard, which is closer to the Founders’ intent than the one applied by Sasse’s critics, he understood and performed his role better than most of his colleagues.

The “pundit” critique oversimplifies his actual record. Sasse served on the Senate Intelligence Committee throughout his tenure, and his work on China there was substantive and largely ahead of the political mainstream. When it was still unfashionable for a Republican to identify Beijing as a generational geopolitical threat rather than an irritating trade partner, Sasse was making that case in the committee rooms that mattered. He had genuine expertise in China’s intelligence operations and, accordingly, used his position, spending considerable time in secure facilities at times when most of his colleagues were busier developing a social media strategy.

Sen. Mark Warner (D-VA), who worked alongside him on the intelligence committee, offered perhaps the most precise characterization of what made Sasse different, telling Scott Pelley on 60 Minutes in April that Sasse “never really thought about things as conservative, liberal. He thought much more about issues, such as the future and the past.” Senate Majority Leader John Thune (R-SD) said Sasse had a “concern not just for today, but for tomorrow and the future” and that he “wasn’t distracted by all the noise that goes around us on a daily basis.” [...]

Levin, who watched Sasse’s tenure closely, offers a candid accounting of his legislative limitations. “It’s true that Ben was not an active legislator, advancing proposals, sponsoring and co-sponsoring legislation, and building coalitions,” he said. “He was active in some key committees, especially the Intelligence Committee, where it seemed to him that active engagement could make a difference. But I think he concluded this was not the case in some of his other committees and that he might be more useful as a critic and observer of the institution. No individual senator gets a lot done right now, and of course, that’s part of the frustration he had.”

But the moments that defined Sasse as a senator were the ones that did not produce legislation, and those are the moments worth examining without the usual condescension.

On the first day of Justice Brett Kavanaugh‘s Supreme Court confirmation hearings in September 2018, the chamber descended almost immediately into the theater that had by then become customary. Protesters disrupted proceedings from the gallery. Democratic senators jockeyed for camera time. The atmosphere was more performance than inquiry. Into this circus, Sasse delivered a 12-minute statement that went viral because it said plainly what almost no one in that room was willing to say: The hysteria around confirmation hearings is a symptom, not the disease. Congress had spent decades delegating its legislative authority to executive agencies and now blamed the courts for filling the vacuum.

“It is predictable now that every confirmation hearing is going to be an overblown, politicized circus,” he said. “And it’s because we’ve accepted a bad new theory about how our three branches of government should work.” The corrective he offered was simple: Congress should pass laws and stand before voters. The executive should enforce those laws. Judges should apply them, not write them. Naturally, no one disagreed out loud.

He delivered a version of the same argument at Justice Amy Coney Barrett‘s hearing in 2020. Neither speech moved the institution. Both captured something true and important about why the institution was failing, and both were widely shared by people who had largely stopped expecting a sitting senator to say anything worth sharing. The Kavanaugh statement was described in this publication at the time as the civics lesson Washington desperately needed. That it needed to be given by a freshman senator to the full Senate Judiciary Committee was Sasse’s real point.

He also understood, more clearly than most of his colleagues, that the Senate’s dysfunction was not incidental but structural. The cameras, he argued, were a bad incentive. The constant travel and time spent fundraising corroded the relationships that make effective governing possible. Most tellingly, he believed that senators had come to treat their office as the purpose of their lives rather than a temporary form of service to something larger. When Pelley noted on 60 Minutes that many senators he knew “would not be able to breathe without that job,” Sasse replied that he feared that was true and that it represented “a much, much deeper problem.” The best title a person could hold, he said, was dad, mom, neighbor, friend. Senator was “a great way to serve. It should be your 11th calling or maybe sixth, but never top.”

When he resigned from the Senate in January 2023 with four years remaining in his term to become president of the University of Florida, many observers treated it as confirmation of the pundit critique: He could not stay the course. The more honest reading is that he had concluded the institution was, as he told Pelley, “very, very unproductive” and that there were better things for him to do. “We didn’t do real things,” he said. “And it felt like the opportunity cost was really high.” He moved to Florida, then stepped down from that post roughly a year and a half later when his wife, Melissa, was diagnosed with epilepsy and required full-time care. The man who had argued that being a senator should rank no higher than sixth on a person’s list of priorities was living accordingly.

Then, on Dec. 23, 2025, he posted the news to X. “Last week I was diagnosed with metastasized, stage-four pancreatic cancer, and am gonna die.” He was 53. Doctors at MD Anderson Cancer Center had cataloged the full spread: lymphoma, vascular cancer, lung cancer, liver cancer, and pancreatic cancer, the point of origin. He had been given three to four months to live. He called it what it was: “Advanced pancreatic is nasty stuff; it’s a death sentence.”

What followed was unexpected, at least to anyone who had expected Sasse to retreat from public life. He launched a podcast called Not Dead Yet. He sat down for a conversation with New York Times columnist Ross Douthat on the latter’s Interesting Times podcast in April, which was released just days after the interview aired and subsequently circulated widely. He appeared on 60 Minutes with Pelley on April 26, his face visibly marked by his medication, a drug called daraxonrasib from Revolution Medicines that had shrunk his tumors by 76% and extended his life by months that were not supposed to exist. He credited the extra time to “providence, prayer, and a miracle drug.”

The Douthat interview was the more intimate of the two conversations and the more remarkable. Douthat asked Sasse at the close whether he felt ready to die. Sasse said he did not feel ready but that he had hope, grounded in his Reformed Christian faith, that he would be with God. The response moved Douthat visibly to tears, something Sasse responded to with his characteristic dry humor. Earlier in the conversation, Sasse reflected on what the disease had given him alongside what it had taken. “I hate pancreatic cancer,” he told Douthat. “I would never wish it on anyone, but I would never want to go back to a time in my life where I didn’t know the prayer of pancreatic cancer. I can’t keep the planets in orbit. I can’t even grow skin on my face.”

The “prayer of pancreatic cancer,” as Sasse uses the phrase, is something like the acknowledgment of dependence that most people spend their healthiest years avoiding. He is not unusual among the terminally ill in arriving at that acknowledgment. He is unusual in the way he has extended it outward, into public argument, into the same institutional critique he was making in November 2015. On 60 Minutes, he was asked what Congress was missing, and he named the artificial intelligence revolution, the future of work, and the complete absence of 2030 or 2050 thinking in either party. Then, without prompting, he returned to the frame he had always used. “The Senate needs to be less like Instagram. The Senate needs to be more deliberative, and that means less smack-down nonsense,” he told Pelley, adding, “The Senate should be plodding, and steady, and boring, and trustworthy.”

by Jay Caruso, Washington Examiner |  Read more:

Image: uncredited via

[ed. I knew very little about Ben Sasse before reading an article about daraxonrasib, the new breakthrough drug given to him in his treatment for aggressive pancreatic cancer. It goes without saying that Congress would be an entirely different place if there were more people like him. See also: Pancreatic cancer just met its match (Works in Progress):]

***

"For most of the last half-century, a diagnosis of metastatic pancreatic cancer was a death sentence. In December 2025, former Nebraska Senator Ben Sasse announced he had been diagnosed with stage four pancreatic cancer that had spread to his lungs, liver and other organs, and was given three to four months to live from the time of diagnosis. With little to lose, he enrolled in a clinical trial for an experimental drug. Four months later, he reported a 76 percent reduction in tumor volume, describing the drug, daraxonrasib, as a ‘miracle’. His face, ravaged by a severe skin rash from the treatment, told a more complicated story. Yet he was alive and grateful to be able to talk to his family.

A few days after Sasse’s interview, in April 2026, Revolution Medicines announced Phase 3 trial results for daraxonrasib showing the drug had roughly doubled survival in patients with metastatic pancreatic cancer compared to standard chemotherapy. For a disease where median survival has long been measured in months and where little had changed for decades, that result represents a genuine turning point.

But the significance extends beyond pancreatic cancer. Daraxonrasib is among the first drugs in an emerging generation designed to target RAS, a protein implicated in roughly a quarter of all human cancers and long considered beyond reach, in all its mutant forms. And it belongs to a broader class of medicines, molecular glues, that are beginning to show what becomes possible when drugs no longer depend on finding a ready-made pocket in their target. Several compounds in this class are now in clinical development, each probing a different protein that previous generations of drugs could not touch."

The Sucker

On a Thursday evening in September, I excused myself from the family dinner table and slipped into my bedroom. I didn’t want my kids to see what I was about to do.

With the door locked behind me, I pulled out my phone and downloaded the DraftKings betting app. I felt a certain thrill as I typed in my debit-card information and deposited $500. The first game of the NFL season was a few minutes away. Anything seemed possible.

I am not, by temperament, a gambling man. As a suburban dad with four kids, a mortgage, and a minivan, I’m more likely to be found wrestling a toddler into a car seat than scouring moneylines or consulting betting touts. And as a practicing Mormon, I am prohibited from indulging in games of chance. Besides, I had always thought of gambling as a waste of time. This makes me an outlier among my generational peers: Since 2018, Americans have wagered more than half a trillion dollars on sports, and roughly half of men ages 18 to 49 have an active account with an online sportsbook.

When I set out to report on the sports-betting industry—its explosive growth, its sudden cultural ubiquity, and what it’s doing to America—my editors thought I should experience the phenomenon firsthand. Mindful of my religious constraints, they proposed a work-around: The Atlantic would stake me $10,000 to gamble with over the course of the upcoming NFL season. The magazine would cover any losses, and—to ensure my ongoing emotional investment—split any winnings with me, 50–50. Surely God would approve of such an arrangement, my editors reasoned, because I wouldn’t be risking my own hard-earned money.

This spiritual loophole intrigued me. But for the sake of my soul, I decided I’d better consult a higher ecclesiastical authority than The Atlantic’s masthead.

A few days later, I sat across from my bishop, explaining the experiment and watching a look of pastoral concern come over his face. After some consideration, he said (a bit tentatively, if I’m being honest), “I don’t think you’re doing anything wrong.” He grasped the difference between gambling with my own money and using my employer’s for research purposes. But he had also seen too many lives wrecked by vice to let me leave without a warning. He told me stories he’d heard about upstanding family men who had let an initially modest gambling habit ruin them, and a cautionary tale about a churchgoing lawyer who developed an unhealthy curiosity about sex work after handling a prostitution case and wound up devastating his family.

I promised the bishop that I would steer clear of slippery slopes. “This will really just be a journalistic exercise,” I assured him.

Fifteen minutes before kickoff, I scrolled through the available wagers on DraftKings in wide-eyed bewilderment. Struggling to make sense of the terminology—Profit boosts? Alternative spreads?—I punched in bets almost at random. I bet that the Eagles would beat the Cowboys by at least nine points, based on the sophisticated premise that the Eagles had won the previous Super Bowl and the Cowboys had not. I placed a bet that Eagles quarterback Jalen Hurts would throw for more than 200 yards, and wagered on something called a “same-game parlay” that would pay out if both Hurts and running back Saquon Barkley scored touchdowns.

Then, after tucking in my kids for the night, I turned on the TV in our bedroom and settled in next to my wife, Annie.

Watching the game was unexpectedly stressful. Toggling among my five different bets—monitoring their progress, weighing live “cash out” options—left me feeling harried and sweaty. Four seconds into the game, I got a taste of the capriciousness of the enterprise when the Eagles’ best defender inexplicably spit on the Cowboys’ quarterback and got himself ejected. Had the Eagles’ chances of beating the spread, and my chances at winning $75, just been expectorated away?

Ever since the advent of sports, humans have found ways to lose money gambling on them.

But the experience was also strangely mesmerizing. For 200 bucks, I had purchased an artificial rooting interest in a game I had no reason to care about. I kept watching even after a weather delay pushed it late into the night, scrolling frenetically next to my sleeping wife in search of angles to exploit with late-game bets. Most of my bets ended up losing, but the long-shot Hurts-Barkley parlay hit, and when the game ended, I calculated that I was up $20.

The next morning, I proudly shared the news with Annie, who high-fived me and immediately began to fantasize about how we would spend my winnings for the season. Could we replace our dying KitchenAid mixer? Remodel the kitchen pantry? Like so many wives before her, she had looked upon my foray into sports gambling with a bemused air of exasperation; now she was seeing a potential upside.

I laughed at her sudden enthusiasm—but I was starting to get ideas myself. I had made $20 on my very first night of gambling. Scale up the wager sizes, multiply across all 272 games in the NFL season, throw in some NBA and college football, and I stood to make—what, $10,000? $20,000? More?

I knew, of course, that I wouldn’t win every bet. But I didn’t see the harm in dreaming. As Annie and I traded home-improvement fantasies, I tried my best not to dwell on the last thing the bishop had said to me: “Be careful.” 

Practically overnight, we took an ancient vice—long regarded as soul-rotting and civilizationally ruinous—put it on everyone’s phone, and made it as normal and frictionless as checking the weather. What could possibly go wrong? [...]

Week Two

Total gambled: $376.00
Down $58.15

If I was going to do this, I decided, I would need a gambling guru—someone to talk me through the basics of sound sports betting (if such a thing existed) and teach me best practices.

The obvious choice was Nate Silver, America’s most famous statistics nerd. Silver first made a name for himself as the founder of 538, an election-forecasting website that accurately predicted the winner of all 50 states in the 2012 presidential campaign. A few years ago, Silver, citing a midlife crisis and political fatigue, discarded the pundit suits, threw on a baseball cap, and started writing more about gambling. He launched a newsletter full of sophisticated sports-betting models and wrote a book about the psychology of successful gamblers. He estimates that he has netted in the “mid–six figures” over the course of his gambling life. If anyone could turn me into a respectable bettor, I figured, it was him.

Before our first call, I sheepishly sent Silver my week-one bet slips. After that first triumphant game, things had gone downhill. Scrolling through DraftKings’ offerings, I had turned into a little kid at a carnival, emptying my parents’ wallet into any ring toss or high striker that caught my eye. I’d taken fliers on games without doing any research, and placed live bets on whatever ESPN happened to be showing when I turned on the TV. On Saturday afternoon, while casually watching a random college-football game with my brother, I bet $10 that the point total wouldn’t go over 52.5, lost, tried to make my money back with a new bet that it wouldn’t go over 61.5, and lost that one too. Of the 14 wagers I’d placed in my first week, I’d won three.

Silver pulled up my slips when we got on the phone, and began to audibly react as he scrolled:

“Okay …”

“Oh.”

“Oh no.” He started laughing.

Is it possible to be emasculated by Nate Silver? Apparently, yes.

Perhaps sensing my humiliation, he tried to soften his assessment. “Look, the nice way to put it is that you’re betting like a recreational bettor.” I took this as a withering insult.

Silver laid out some basic realities of the sports-betting economy. The books effectively charge you about 4.5 percent for every bet you place, he explained, which means it isn’t enough to win 50.1 percent of the time; you have to win 52.5 percent of your bets just to break even, and that’s before taxes. My most obvious mistake, he said, was that I was using only DraftKings. To find edges, I would need to shop for lines across at least three or four books every week.

He gave me other tips, too: Avoid “prop bets” on individual players (Josh Allen to rush for more than 50 yards) and multi-leg parlays, which pay out only if every outcome hits (the Chiefs cover the spread, the Ravens win, and the Chargers score more than 24 points). Props and parlays are how sportsbooks generate most of their profits. “They’re suckers’ bets,” Silver said, which made sense, given that I had already placed several of them.

Live betting—placing wagers in the middle of games—was also a bad idea, he told me, because it leads to gambling based on emotion more than logic. Also, televised games are broadcast on a delay, which means the sportsbooks can adjust lines before you even see what has happened on the field. You are, in effect, betting against people who live 20 seconds in the future.

To guard against emotional betting, Silver suggested a Tuesday-morning ritual: I should sit in a quiet place, study the lines for that week’s games, gather information on injury reports and weather forecasts, and then place $100 bets on the six or seven games I liked best.

Before we hung up, I asked Silver what kind of profit would make it a successful season for me.

He seemed confused by the question. “If you make one penny, that would be better than 98 percent of people over an entire season,” Silver answered, as if this were obvious.

I was taken aback. Hadn’t Silver himself made hundreds of thousands of dollars gambling? Yes, he said, but that was mostly from poker tournaments. Sports betting was a game of razor-thin margins and microscopic edges. NFL football was among the hardest sports to win money on—the lines were too sharp, the teams too evenly matched. Silver told me that, even with his quantish models and prognosticatory brilliance, he would consider it cause to celebrate if he broke even on the season.

by McKay Coppins, The Atlantic |  Read more:
Image: Tyler Comrie/Getty

[ed. See also: The Online Sports Gambling Experiment Has Failed (DS).]

America and Public Disorder, and "The Kill Line"

Two weeks ago, on the blue line to O’Hare, my car had two men smoking joints, a broken woman, her eyes dilated and blank, sitting in a nest of filthy bags smelling of sewage, and a man barking into the void, shirtless, who was washing himself with flour tortillas, which would disintegrate, littering the subway floor, before he took out another and began the same process. This didn't shock me, or anyone else around me, since I'd seen some variation of this dystopian scene on every Chicago metro line I'd ridden, every pedestrian walkway I'd passed through, and on most street corners.

Three weeks ago, in Duluth, half the riders on every bus I took were mentally tortured and/or intoxicated. The downtown Starbucks, pedestrian malls, and shuttered doorways of vacated buildings all housed broken people. Same in Indianapolis, El Paso, New York City, Jacksonville, LA, Phoenix, and almost every community I’ve been to in the U.S., save for those gated by wealth.

An epidemic of mental illness and/or addiction plays out in the U.S. in public, with our streets, buses, parking lots, McDonald’s, parks, and Starbucks as ad hoc institutions for the broken, addicted, and tortured.That is not the case for the rest of the world, including where I am now, Seoul. My train from the airport was spotless, and so is the ten-mile river park I walk each day here, which given that large parts of it are beneath roadways is especially impressive. In the U.S. it would have impromptu homes of tents, cardboard, and tarps, smell of urine, and the exercise spots that dot its length probably couldn’t exist because of a fear of being vandalized.

You can learn more about the U.S. by traveling overseas and comparing, and five years of that has taught me we accept far too much public disorder.

We are the world’s richest country, and yet our buses, parking lots, and city streets are filthy, chaotic, and threatening. Antisocial and abnormal behavior, open addiction, and mentally tortured people are common in almost every community regardless of size.

I’ve written about this many times before, because it is so striking, and it has widespread consequences, beyond the obvious moral judgement that a society should simply not be this way.

It’s a primary reason why we shy away from dense walkable spaces and instead move towards suburban sprawl. People in the U.S. don’t respect, trust, or want to be around other random citizens, out of fear and disgust. Japanese/European style urbanism—density, fantastic public transport, mixed-use zoning, that so many American tourists admire—can't happen here because there is a fine line between vibrant streets and squalid ones, and that line is public trust. The U.S. is on the wrong side of it. Simply put, nobody wants to be accosted by a stranger, no matter how infrequent, and until that risk is close to nil, people will continue edging towards isolated living.

It is why we “can’t have nice things” because we have to construct our infrastructure to be asshole-proof, and so we don’t build anything or build with a fortress mentality, stripping our public spaces down to the austere and utilitarian, emptying them of anything that can be vandalized.

The canonical example of this is La Sombrita, the laughably expensive Los Angeles “bus stop” that was a single pole to provide shade and security lighting, but did neither. La Sombrita exists precisely because it doesn’t do anything, which is the end result of a decades-long process of defensive construction. If you build a nice bus stop it is either immediately broken or turned into shelters for the destitute, and so you stop building those.

Another nice thing we don’t have in the U.S. is public restrooms. We don’t have them out of a justified fear of abuse, which is the same reason many Starbucks lock their restrooms. McDonald’s does this as well, depending on the location, and also even strips them of mirrors in the especially bad communities, to discourage people from using them for an hour-long morning toilet, as well as breaking the mirrors just for the hell of it.

This lack of public restrooms became an issue on Twitter when the latest round of debate about disorder in the U.S. was kicked off when a tweeter noted how offensive it was to have seen someone urinating in a crowded New York subway car.

This debate brought out a lot of absurd arguments, mostly from those trying to shrug it off or suggest it was simply the price of living in a big city.

No, the rest of the world doesn’t tolerate the amount of antisocial behavior we in the U.S. do. If someone were to piss on a subway anywhere else in the world, and very very few ever would want to (more on why below), they are removed from society for a period of time.

We however let people who aren’t mentally competent continue to engage in self-destructive and aberrant behavior without removing them, which consequently ruins it for everyone else, except those wealthy enough to build their own private islands of comfort.

Someone peeing on the subway is not of sound mind, and it isn’t normal behavior by any measure. It’s a sign of distress that should cause an intervention—by police, social workers, whoever—that mandates them into an institution for a period of time, until they regain sanity and stability. For someone actively psychotic —civil commitment to psychiatric hospital. For violent individuals refusing treatment—secure prison facilities with mandatory programs. For severe addiction—medical detox and residential treatment without the ability to walk away.

They should not be allowed to do whatever they want because they cannot control themselves enough to have that freedom. Someone shouting at strangers, someone washing themselves with flour tortillas, someone punching at the air voicing threats shouldn’t, for their own safety and others, be out roaming the streets. [...]

I’ve been very careful up to now not to use the word homeless, because it’s become an overly broad category that covers families in motels with Section 8 vouchers, people sleeping on friends’ couches until they can get back on their feet, mothers with children in long-term shelters, and then those who live in tents under bridges or sleep in a soiled sleeping bag.

Eighty-five percent (or so) of those in this broad category are not causing problems. They are, like most everyone else, doing their best to get by and better themselves. Sure, they have more complicated and chaotic lives than most, but they try to play by the rules as best they can.

Our problems in public spaces come from the fifteen percent or so who fall into the last group—the stubbornly intransigent—which are people who have options for housing but turn them down for a variety of reasons, some driven by mental demons, some by an overwhelming desire to always be on drugs, some simply out of preference to be alone. Others in this category have been ejected from housing because of continual violent and threatening behavior.

They are not, by almost any metric, of sound mind, and shouldn’t be granted the full privileges other citizens have.

The cover photo is John, and he is in this category. He had set himself on fire the day before I met him, freebasing a perc 30, and refused to go to the hospital because he didn’t want to lose his favorite spot behind the garbage bin, since it was only a block away from dealers and perfect to piss in. He had a government room he didn’t use because catching on fire (something he did every now and then) set off smoke alarms. He also thought it was cursed and monitored by the same people who had held him captive on an island in the middle of the Pacific—an island he escaped from three months before by swimming the four hundred miles. He showed me an arm, covered with burns, that he claimed was where a shark had bit him.

John should be mandated into a prison, a mental institution, or a rehab clinic, until he is competent enough to be on his own, not out on the streets in mental and physical pain, setting himself on fire. It is as simple as that, although I understand a change like this comes with additional nuanced policy debate. As for costs, it is more a question of redirecting what we spend rather than finding additional money, because we already spend an immense amount on this problem—the New York City budget for homeless services is four billion—without 'solving' it.

Even if you put aside the destruction this type of behavior has done to broader society, and your concerns are only focused on the health and welfare of the stubbornly intransigent, then our current system is still deeply wrong. We are not providing them justice by allowing them to choose a public display of mental misery, where the self harm they can do is far greater than when being monitored.

Beneath all this discussion is the additional question of why we in the U.S. have so many mentally unstable people, why so many are addicted to drugs, why so many people are OK with doing shocking things.

by Chris Arnade, Walks the World | Read more:
Images: X/uncredited

[ed. We've lost the plot. Or not. Maybe this is just an accurate reflection of this country's priorities over the last 50 years or so. Even worse, with AI just around the corner, it's going to get a lot worse unless our government starts working for its people again (and our people start working for our country again, beginning with acknowledging their own civic duties and responsibilities that go beyond simply paying taxes, gaming the system, and trying to make as much money as possible). From the comments:]

***

One of the things travel does best is remove the normalization filter we build at home. When you move between countries long enough, patterns that once felt “just how things are” start to look like choices societies have made - or failed to make.

What strikes me in pieces like this is not the comparison itself, but the discomfort it creates. Clean transit systems, safe public spaces, and functioning streets aren’t cultural miracles; they’re outcomes of priorities, incentives, and sustained public decisions. When those systems break down, the result isn’t abstract policy failure - it’s visible human suffering playing out in the most ordinary places.

Travel doesn’t just show us new landscapes. It quietly exposes which problems we’ve decided to tolerate.

***

[ed. See also: The Kill Line: Why China Is Suddenly Obsessed With American Poverty (NYT).]

Chinese commentators are talking a lot these days about poverty in the United States, claiming China’s superiority by appropriating an evocative phrase from video game culture.

The phrase, “kill line,” is used in gaming to mark the point where the condition of opposing players has so deteriorated that they can be killed by one shot. Now, it has become a persistent metaphor in Communist Party propaganda.

“Kill line” has been used repeatedly on social media and commentary sites, as well as news outlets linked to the state. It has gained traction in China to depict the horror of American poverty — a fatal threshold beyond which recovery to a better life becomes impossible. The phrase is used as a metaphor to encompass homelessness, debt, addiction and economic insecurity. In its official use, the “kill line” hovers over the heads of Americans but is something Chinese people don’t have to fear. [...]

The power is in the simplicity of what it describes: an abrupt threshold where misery begins and a happy life is irreversibly lost. The narrative is meant to offer China’s people emotional relief while attempting to deflect criticism of its leaders.

The worse things look across the Pacific, the logic of the propaganda goes, the more tolerable present struggles become. [...]

The fact is that societal inequality is a problem in both China and the United States. And the American economy no doubt leaves many people in fragile positions. The causes are complex.

Yet in China, poverty is experienced and perceived differently. In most Chinese cities, street begging and visible homelessness are tightly managed, making them far less prominent in daily life. Many urban residents encounter such scenes only through foreign reporting, rebroadcast by Chinese state media, about the United States and other places. [...]

When I was growing up in China in the early 1980s, my family subscribed to China Children’s News, which ran a weekly column with a simple slogan: “Socialism is good; capitalism is bad.” It described seniors in American cities scavenging for food, and homeless people freezing to death. Those stories were not invented, but they lacked context and were presented as the dominant experiences in American society. Much of Chinese society was still closed off from the world, and reliable information was scarce.

That many people accepted such narratives was hardly surprising. What’s striking is that similar portrayals continue to resonate today, when access to information is relatively much greater despite state control.

The formula is simple: magnify foreign suffering to deflect from domestic problems. That approach is taking shape today around the “kill line” metaphor.

The phrase is believed to have been first popularized in this new context on the Bilibili video platform in early November by a user known as Squid King. In a five-hour video, he stitched together what he claimed were firsthand encounters of poverty from time he spent in the United States. His video used scenes of children knocking on doors on a cold Halloween night asking for food, delivery workers suffering from hunger because of their meager wages and injured laborers discharged from hospitals because they could not pay.

The scenes were presented not as isolated cases but as evidence of a system: Above the “kill line,” life continues; below it, society stops treating people as human.

The narrative spread beyond the Squid King video, and many people online repeated his anecdotes. Essays on the nationalist news site Guancha and China’s biggest social media platform, WeChat, described the “kill line” as the “real operating logic” of American capitalism. [...]

In many of the commentaries, anecdotes about Americans experiencing abrupt financial crises are followed by comparisons with China. Universal basic health care, minimum subsistence guarantees and poverty alleviation campaigns are cited as evidence that China does not permit anyone to fall into sudden distress.

“China’s system will not allow a person to be ‘killed’ by a single misfortune,” one commentary from a provincial propaganda department states.

Many readers expressed shock at American poverty and gratitude for China’s system. “At least we have a safety net,” said one commenter...

“A topic does not gain traction simply because people are foolish,” one person wrote on WeChat. “Often, it spreads because confronting reality is harder.”

by Li Yuan, NY Times |  Read more:

Image: Doris Liou

Tomorrow’s Smart Pills Will Deliver Drugs and Take Biopsies

One day soon, a doctor might prescribe a pill that doesn’t just deliver medicine but also reports back on what it finds inside you—and then takes actions based on its findings.

Instead of scheduling an endoscopy or CT scan, you’d swallow an electronic capsule smaller than a multivitamin. As it travels through your digestive system, it could check tissue health, look for cancerous changes, and send data to your doctor. It could even release drugs exactly where they’re needed or snip a tiny biopsy sample before passing harmlessly out of your body.

This dream of a do-it-all pill is driving a surge of research into ingestible electronics: smart capsules designed to monitor and even treat disease from inside the gastrointestinal (GI) tract. The stakes are high. GI diseases affect tens of millions of people worldwide, including such ailments as inflammatory bowel disease, celiac disease, and small intestinal bacterial overgrowth. Diagnosis often involves a frustrating maze of blood tests, imaging, and invasive endoscopy. Treatments, meanwhile, can bring serious side effects because drugs affect the whole body, not just the troubled gut.

If capsules could handle much of that work—streamlining diagnosis, delivering targeted therapies, and sparing patients repeated invasive procedures—they could transform care. Over the past 20 years, researchers have built a growing tool kit of ingestible devices, some already in clinical use. These capsule-shaped devices typically contain sensors, circuitry, a power source, and sometimes a communication module, all enclosed in a biocompatible shell. But the next leap forward is still in development: autonomous capsules that can both sense and act, releasing a drug or taking a tissue sample.

That’s the challenge that our lab—the MEMS Sensors and Actuators Laboratory (MSAL) at the University of Maryland, College Park—is tackling. Drawing on decades of advances in microelectromechanical systems (MEMS), we’re building swallowable devices that integrate sensors, actuators, and wireless links in packages that are small and safe enough for patients. The hurdles are considerable: power, miniaturization, biocompatibility, and reliability, to name a few. But the potential payoff will be a new era of personalized and minimally invasive medicine, delivered by something as simple as a pill you can swallow at home. [...]

Targeted drug delivery is one of the most compelling applications for ingestible capsules. Many drugs for GI conditions—such as biologics for inflammatory bowel disease—can cause serious side effects that limit both dosage and duration of treatment. A promising alternative is delivering a drug directly to the diseased tissue. This localized approach boosts the drug’s concentration at the target site while reducing its spread throughout the body, which improves effectiveness and minimizes side effects. The challenge is engineering a device that can both recognize diseased tissue and deliver medication quickly and precisely.

With other labs making great progress on the sensing side, we’ve devoted our energy to designing devices that can deliver the medicine. We’ve developed miniature actuators—tiny moving parts—that meet strict criteria for use inside the body: low power, small size, biocompatibility, and long shelf life.

Some of our designs use soft and flexible polymer “cantilevers” with attached microneedle systems that pop out from the capsule with enough force to release a drug, but without harming the intestinal tissue. While hollow microneedles can directly inject drugs into the intestinal lining, we’ve also demonstrated prototypes that use the microneedles for anchoring drug payloads, allowing the capsule to release a larger dose of medication that dissolves at an exact location over time.

In other experimental designs, we had the microneedles themselves dissolve after injecting a drug. In still others, we used microscale 3D printing to tailor the structure of the microneedles and control how quickly a drug is released—providing either a slow and sustained dose or a fast delivery. With this 3D printing, we created rigid microneedles that penetrate the mucosal lining and gradually diffuse the drug into the tissue, and soft microneedles that compress when the cantilever pushes them against the tissue, forcing the drug out all at once.

by Reza Ghodssi, Justin Stine, Luke Beardslee, IEEE Spectrum |  Read more:

Image: Maximilian Franz/Engineering at Maryland Magazine

Alcohol Death Rates in Europe

Source: Institute for Health Metrics and Evaluation (OWID)
via:
[ed. A few surprises.]

"Alcohol death rates in Europe. Apparently very low in cultures where drunkenness is frowned upon and where alcohol is only consumed in company of others and served alongside meals. Spain and Italy for example." via:

I Regret to Inform You that the FDA is FDAing Again

I had high hopes and low expectations that the FDA under the new administration would be less paternalistic and more open to medical freedom. Instead, what we are getting is paternalism with different preferences. In particular, the FDA now appears to have a bizarre anti-vaccine fixation, particularly of the mRNA variety (disappointing but not surprising given the leadership of RFK Jr.).

The latest is that the FDA has issued a Refusal-to-File (RTF) letter to Moderna for their mRNA influenza vaccine, mRNA-1010. An RTF means the FDA has determined that the application is so deficient it doesn’t even warrant a review. RTF letters are not unheard of, but they’re rare—especially given that Moderna spent hundreds of millions of dollars running Phase 3 trials enrolling over 43,000 participants based on FDA guidance, and is now being told the (apparently) agreed-upon design was inadequate. [...]

In context, this looks like the regulatory rules of the game are being changed retroactively—a textbook example of regulatory uncertainty destroying option value. STAT News reports that Vinay Prasad personally handled the letter and overrode staff who were prepared to proceed with review. Moderna took the unusual step of publicly releasing Prasad’s letter—companies almost never do this, suggesting they’ve calculated the reputational risk of publicly fighting the FDA is lower than the cost of acquiescing.

Moreover, the comparator issue was discussed—and seemingly settled—beforehand. Moderna says the FDA agreed with the trial design in April 2024, and as recently as August 2025 suggested it would file the application and address comparator issues during the review process.

Finally, Moderna also provided immunogenicity and safety data from a separate Phase 3 study in adults 65+ comparing mRNA-1010 against a licensed high-dose flu vaccine, just as FDA had requested—yet the application was still refused.

What is most disturbing is not the specifics of this case but the arbitrariness and capriciousness of the process. The EU, Canada, and Australia have all accepted Moderna’s application for review. We may soon see an mRNA flu vaccine available across the developed world but not in the United States—not because it failed on safety or efficacy, but because FDA political leadership decided, after the fact, that the comparator choice they inherited was now unacceptable.

The irony is staggering. Moderna is an American company. Its mRNA platform was developed at record speed with billions in U.S. taxpayer support through Operation Warp Speed — the signature public health achievement of the first Trump administration. The same government that funded the creation of this technology is now dismantling it. In August, HHS canceled $500 million in BARDA contracts for mRNA vaccine development and terminated a separate $590 million contract with Moderna for an avian flu vaccine. Several states have introduced legislation to ban mRNA vaccines. Insanity.

The consequences are already visible. In January, Moderna’s CEO announced the company will no longer invest in new Phase 3 vaccine trials for infectious diseases: “You cannot make a return on investment if you don’t have access to the U.S. market.” Vaccines for Epstein-Barr virus, herpes, and shingles have been shelved. That’s what regulatory roulette buys you: a shrinking pipeline of medical innovation.

An administration that promised medical freedom is delivering medical nationalism: fewer options, less innovation, and a clear signal to every company considering pharmaceutical investment that the rules can change after the game is played. And this isn’t a one-product story. mRNA is a general-purpose platform with spillovers across infectious disease and vaccines for cancer; if the U.S. turns mRNA into a political third rail, the investment, talent, and manufacturing will migrate elsewhere. America built this capability, and we’re now choosing to export it—along with the health benefits.

by Alex Tabarrok, Marginal Revolution |  Read more:

Image: Brian Snyder/Reuters

[ed. See also: F.D.A. Refuses to Review Moderna Flu Vaccine (NYT); and, Trump official overruled FDA scientists to reject Moderna’s flu shot (Ars Technica).]

Why Even the Healthiest People Hit a Wall at Age 70

Are we currently determining how much of aging is lifestyle changes and interventions and how much of it is basically your genetic destiny?

 

[Transcript:] We are constantly being bombarded with health and lifestyle advice at the moment. I feel like I cannot open my social media feeds without seeing adverts for supplements or diet plans or exercise regimes. And I think that this really is a distraction from the big goals of longevity science. This is a really difficult needle to thread when it comes to talking about this stuff because I'm a huge advocate for public health. I think if we could help people eat better, if we could help 'em do more exercise, if we could help 'em quit smoking, this would have enormous effects on our health, on our economies all around the world. But this sort of micro-optimization, these three-hour long health podcasts that people are digesting on a daily basis these days, I think we're really majoring in the minors. We're trying to absolutely eke out every last single thing when it comes to living healthily. And I think the problem is that there are real limits to what we can do with health advice. 

So for example, there was a study that came out recently that was all over my social media feeds. And the headline was that by eating the best possible diet, you can double your chance of aging healthily. But I decided to dig into the results table. The healthiest diet was something called the Alternative Healthy Eating Index or AHEI. And even the people who are sticking most closely to this best diet, according to this study, the top 20% of adherence to the AHEI, only 13.6% of them made it to 70 years old without any chronic diseases. That means that over 85% of the people sticking to the best diet, according to this study, got to the age of 70 with at least something wrong with them. And that shows us that optimizing diet only has so far it can go. 

We're not talking about immortality or living to 120 here. If you wanna be 70 years old and in good enough health to play with your grandkids, I cannot guarantee that you can do that no matter how good your diet is. And that's why we need longevity medicine to help keep people healthier for longer. And actually, I think even this idea of 120, 150-year-old lifespans, you know, immortality even as a word that's often thrown around, I think the main thing we're trying to do is get people to 80, 90 years old in good health. 'cause we already know that most people alive today, when they reach that age, are unfortunately gonna be frail. They're probably gonna be suffering from two or three or four different diseases simultaneously. And what we wanna do is try and keep people healthier for longer. And by doing that, they probably will live longer but kind of as a side effect. 

If you look at photographs of people from the past, they often look older than people in the present day who are the same age. And part of these are these terrible fashion choices that people made in the past. And we can look back and, you know, understand the mistakes they've made with hindsight. But part of that actually is aging biology. I think the fact that people can be different biological ages at the same chronological ages, something that's really quite intuitive. All of us know people who've waltzed into their 60s looking great and, you know, basically as fit as someone in their 40s or 50s. And we know similar people who have also gone into their 60s, but they're looking haggard, they've got multiple different diseases, they're already struggling through life. 

In the last decade, scientists have come up with various measures of what's called biological age as distinct from chronological age. So your chronological age is just how many candles there are on your birthday cake. And obviously, you know, most of us are familiar with that. But the idea of biological age is to look inside your cells, look inside your body, and work out how old you are on a biological level. Now we aren't perfect at doing this yet, but we do have a variety of different measures. We can use blood tests, we can use what are called epigenetic tests, or we can do things that are far more sort of basic and functional, how strong your grip is declines with age. And by comparing the value of something like your grip strength to an average person of a given age, we can assign you a biological age value. And I think the ones that are getting the most buzz at the moment within the scientific community, but also all around the internet, are these epigenetic age tests. 

So the way that this works is that you'll take a blood test or a saliva sample and scientists will measure something about your epigenome. So the genome is your DNA, it's the instruction manual of life. And the epigenome is a layer of chemistry that sits on top of your genome. If you think of your DNA is that instruction manual, then the epigenome is the notes in the margin. It's the little sticky notes that have been stuck on the side and they tell the cell which DNA to use at which particular time. And we know that there are changes to this epigenome as you get older. And so by measuring the changes in the epigenome, you can assign someone a biological age. 

At the moment, these epigene clocks are a really great research tool. They're really deepening our understanding of biological aging in the lab. I think the problem with these tests as applied to individuals is we don't know enough about exactly what they're telling us. We don't know what these individual changes in epigenetic marks mean. We know they're correlated with age, but what we don't know is if they're causally related. And in particular, we don't know if you intervene, if you make a change in your lifestyle, if you start taking a certain supplement and that reduces your biological age. We don't know whether that actually means you're gonna dilate or whether it means you're gonna stay healthier for longer or whether you've done something that's kind of adjacent to that. And so we need to do more research to understand if we can causally impact these epigenetic measures. (...)

Machine learning and artificial intelligence are gonna be hugely, hugely important in understanding the biology of aging. Because the body is such a complicated system that in order to really understand it, we're gonna need these vast computer models to try and decode the data for us. The challenge is that what machine learning can do at the moment is it can identify correlations. So it can identify things that are associated with aging, but it can't necessarily tell us what's causing something else. So for example, in the case of these epigenetic clocks, the parts of the epigenome that change with age have been identified because they correlate. But what we don't know is if you intervene in any one of these individual epigenetic marks, if you move it in the direction of something younger, does that actually make people healthier? And so what we need to do is more experiments where we try and work out if we can intervene in these epigenetic, in these biological clocks, can we make people live healthier for longer? 

Over the last 10 or 15 years, scientists have really started to understand the fundamental underlying biology of the aging process. And they broke this down into 12 what are called hallmarks of aging. One of those hallmarks is the accumulation of senescent cells. Now senescent is just a biological technical term for old. These are cells that accumulate in all of our bodies as the years go by. And scientists have noticed that these cells seem to drive a range of different diseases as we get older. And so the idea was what if we could remove these cells and leave the rest of the cells of the body intact? Could that slow down or even partially reverse the aging process? And scientists identified drugs called it senolytic drugs. 

These are drugs that kill those senescent cells and they tried them out in mice and they do indeed effectively make the mice biologically younger. So if you give mice a course of senolytic drugs, it removes those senescent cells from their body. And firstly, it makes them live a bit longer. That's a good thing if you're slowing down the aging process, the basic thing you want to see. But it's not dragging out that period of frailty at the end of life. It's keeping the mice healthier for longer so they get less cancer, they get less heart disease, they get fewer cataracts. The mice are also less frail. They basically send the mice to a tiny mouse-scale gym in these experiments. And the mice that have been given the drugs, they can run further and faster on the mousey treadmills that they try them out on. 

It also seems to reverse some of the cognitive effects that come along with aging. So if you put an older mouse in a maze, it's often a bit anxious, doesn't really want to explore. Whereas a younger mouse is desperate to, you know, run around and find the cheese or whatever it is mice doing in mazes. And by giving them these senolytic drugs, you can unlock some of that youthful curiosity. And finally, these mice just look great. You do not need to be an expert mouse biologist to see which one has had the pills and which one hasn't. They've got thicker fur. They've got plumper skin. They've got brighter eyes. They've got less fat on their bodies. And what this shows us is that by targeting the fundamental processes of aging, by identifying something like senescent cells that drives a whole range of age-related problems, we can hit much perhaps even all of the aging process with a single treatment. 

Senescent cells are, of course, only one of these 12 hallmarks of aging. And I think in order to both understand and treat the aging process, we're potentially gonna only treatments for many, perhaps even all of those hallmarks. There's never gonna be a single magic pill that can just make you live forever. Aging is much, much more complicated than that. But by understanding this relatively short list of underlying processes, maybe we can come up with 12, 20 different treatments that can have a really big effect on how long we live. 

One of the most exciting ideas in longevity science at the moment is what's called cellular reprogramming. I sometimes describe this as a treatment that has fallen through a wormhole from the future. This is the idea that we can reset the biological clock inside of our cells. And the idea first came about in the mid 2000s because there was a scientist called Shinya Yamanaka who was trying to find out how to turn regular adult body cells all the way back to the very beginning of their biological existence. And Yamanaka and his team were able to identify four genes that you could insert into a cell and turn back that biological clock. 

Now, he was interested in this from the point of view of creating stem cells, a cell that can create any other kind of cell in the body, which we might be able to use for tissue repair in future. But scientists also noticed, as well as turning back the developmental clock on these cells, it also turns back the aging clock, cells that are given these four Yamanaka factors actually are biologically younger than cells that haven't had the treatment. And so what scientists decided to do was insert these Yamanaka factor genes into mice. 

Now if you do this in a naive way, so there's genes active all the time, it's actually very bad news for the mice, unfortunately. because these stem cells, although they're very powerful in terms of what kind of cell they can become, they are useless at being a liver cell or being a heart cell. And so the mice very quickly died of organ failure. But if you activate these genes only transiently, and the way that scientists did it the first time successfully was essentially to activate them at weekends. So they produced these genes in such a way that they could be activated with the drug and they gave the mice the drug for two days of the week, and then gave them five days off so the Yamanaka factors were then suppressed. They found that this was enough to turn back the biological clock in those cells, but without turning back the developmental clock and turn them into these stem cells. And that meant the mice stayed a little bit healthier. We now know that they can live a little bit longer with this treatment too.

Now the real challenge is that this is a gene therapy treatment. It involves delivering four different genes to every single cell in your body. The question is can we, with our puny 2020s biotechnology, make this into a viable treatment, a pill even, that we can actually use in human beings? I really think this idea of cellular reprogramming appeals to a particular tech billionaire sort of mentality. The idea that we can go in and edit the code of life and reprogram our biological age, it's a hugely powerful concept. And if this works, the fact that you can turn back the biological clock all the way to zero, this really is a very, very cool idea. And that's what's led various different billionaires from the Bay Area to invest huge, huge amounts of money in this. 

Altos Labs is the biggest so-called startup in this space. And I wouldn't really call it a startup 'cause it's got funding of $3 billion from amongst other people, Jeff Bezos, the founder of Amazon. Now I'm very excited about this because I think $3 billion is enough to have a good go and see if we can turn this into a viable human treatment. My only concern is that epigenetics is only one of those hallmarks of aging. And so it might be the case that we solve aging inside our individual cells, but we leave other parts of the aging process intact. (...)

Probably the quickest short-term wins in longevity science are going to be repurposed existing drugs. And the reason for this is because we spent many, many years developing these drugs. We understand how they work in humans. We understand a bit about their safety profile. And because these molecules already exist, we've just tried them out in mice, in, you know, various organisms in the lab and found that a subset of them do indeed slow down the aging process. The first trial of a longevity drug that was proposed in humans was for a drug called metformin, which is a pre-existing drug that we prescribe actually for diabetes in this case, and has some indications that it might slow down the aging process in people. (...)

I think one of the ones that's got the most buzz around it at the moment is a drug called rapamycin. This is a drug that's been given for organ transplants. It's sometimes used to coat stents, which these little things that you stick in the arteries around your heart to expand them if you've got a contraction of those arteries that's restricting the blood supply. But we also know from experiments in the lab that can make all kinds of different organisms live longer, everything from single-cell yeast, to worms, to flies, to mice, to marmoset, which are primates. They're very, very evolutionarily close to us as one of the latest results. 

Rapamycin has this really incredible story. It was first isolated in bacteria from a soil sample from Easter Island, which is known as Rapa Nui in the local Polynesians. That's where the drug gets its name. And when it was first isolated, it was discovered to be antifungal. It could stop fungal cells from growing. So that was what we thought we'd use it for initially. But when the scientists started playing around with in the lab, they realized it didn't just stop fungal cells from growing. It also stopped many other kinds of cells as well, things like up to and including human cells. And so the slight disadvantage was that if you used it as an antifungal agent, it would also stop your immune cells from being able to divide, which is obviously be a bit of a sort of counterintuitive way to try and treat a fungal disease. So scientists decided to use it as an immune suppressant. It can stop your immune system from going haywire when you get an organ transplant, for example, and rejecting that new organ. 

It is also developed as an anti-cancer drug. So if it can stop cells dividing or cancer as cells dividing out of control. But the way that rapamycin works is it targets a fundamental central component of cellular metabolism. And we noticed that that seemed to be very, very important in the aging process. And so by tamping it down by less than you would do in a patient where you're trying to suppress their immune system, you can actually rather than stopping the cell dividing entirely, you can make it enter a state where it's much more efficient in its use of resources. It starts this process called autophagy, which is Greek for self-eating, autophagy. And that means it consumes old damaged proteins, and then recycles them into fresh new ones. And that actually is a critical process in slowing down aging, biologically speaking. And in 2009, we found out for the first time that by giving it to mice late in life, you could actually extend their remaining lifespan. They live by 10 or 15% longer. And this was a really incredible result. 

This was the first time a drug had been shown to slow down aging in mammals. And accordingly, scientists have become very, very excited about it. And we've now tried it in loads of different contexts and loads of different animals and loads of different organisms at loads of different times in life. You can even wait until very late in a mouse lifespan to give it rapamycin and you still see most of that same lifespan extension effect. And that's fantastic news potentially for us humans because not all of us, unfortunately, can start taking a drug from birth 'cause most of us were born quite a long time ago. But rapamycin still works even if you give it to mice who are the equivalent of 60 or 70 years old in human terms. And that means that for those of us who are already aged a little bit, Rapamycin could still help us potentially. And there are already biohackers out there trying this out for themselves, hopefully with the help of a doctor to make sure that they're doing everything as safely as possible to try and extend their healthy life. And so the question is: should we do a human trial of rapamycin to find out if it can slow down the aging process in people as well? (...)

We've already got dozens of ideas in the lab for ways to slow down, maybe even reverse the age of things like mice and cells in a dish. And that means we've got a lot of shots on goal. I think it'll be wildly unlucky if none of the things that slow down aging in the lab actually translate to human beings. That doesn't mean that most of them will work, probably most of them won't, but we only need one or two of them to succeed and really make a big difference. And I think a great example of this is GLP-1 drugs, the ozempics, the things that are allowing people to suddenly lose a huge amount of weight. We've been looking for decades for these weight loss drugs, and now we finally found them. It's shown that these breakthroughs are possible, they can come out of left field. And all we need to do in some cases is a human trial to find out if these drugs actually work in people. 

And what that means is that, you know, the average person on planet earth is under the age of 40. They've probably got 40 or 50 years of life expectancy left depending on the country that they live in. And that's an awful lot of time for science to happen. And if then in the next 5 or 10 years, we do put funding toward these human trials, we might have those first longevity drugs that might make you live one or two or five years longer. And that gives scientists even more time to develop the next treatment. And if we think about some more advanced treatments, not just drugs, things like stem cell therapy or gene therapy, those things can sound pretty sci-fi. But actually, we know that these things are already being deployed in hospitals and clinics around the world. They're being deployed for specific serious diseases, for example, where we know that a single gene can be a problem and we can go in and fix that gene and give a child a much better chance at a long, healthy life. 

But as we learn how these technologies work in the context of these serious diseases, we're gonna learn how to make them effective. And most importantly, we're gonna learn how to make them safe. And so we could imagine doing longevity gene edits in human beings, perhaps not in the next five years, but I think it'll be foolish to bet against it happening in the next 20 years, for example. 

by Andrew Steele, The Big Think |  Read more:

Image: Yamanka factors via:

[ed. See also: Researchers Are Using A.I. to Decode the Human Genome (NYT).]