Category: Philanthropy

The Efficacy of Personalized Drugs Designed for Only One Patient Cannot Be Tested by Randomized Double-Blind Clinical Trials (RCTs)

We know that there are times when therapies work for some patients, but not for others. But clinical trials often do not account for such differences. If the effects of the new drug are not widespread enough among the general population, the trial will be deemed a failure, and the F.D.A. will not allow the drug to be taken even by the patients who would have benefitted from it. Maybe the solution is liberty. Allow physicians liberty on what therapies to suggest, and patients liberty on what therapies to try. This especially makes sense when the disease is dire and no effective therapy is yet widely known.

Many predict that we are moving toward personalized medicine. We need less regulation and more liberty so personalized medicine can progress, and more patients can be more quickly cured of more diseases. We need a sense of urgency in requesting liberty.

(p. D3) A new drug, created to treat just one patient, has pushed the bounds of personalized medicine and has raised unexplored regulatory and ethical questions, scientists reported on Wednesday [Oct. 9, 2019].

The drug, described in The New England Journal of Medicine, is believed to be the first “custom” treatment for a genetic disease. It is called milasen, named after the only patient who will ever take it: Mila (mee-lah) Makovec, who lives with her mother, Julia Vitarello, in Longmont, Colo.

. . .

Ms. Vitarello . . . set up Mila’s Miracle Foundation and was appealing for donations on GoFundMe. So, she began fund-raising in earnest, eventually raising $3 million for a variety of research efforts.

Dr. Yu’s team oversaw development of the drug, tested it in rodents, and consulted with the Food and Drug Administration. In January 2018, the agency granted permission to give the drug to Mila. She got her first dose on Jan. 31, 2018.

With continued treatments, the number of seizures has diminished so much that the girl has between none and six a day, and they last less than a minute.

Milasen is believed to be the first drug developed for a single patient (CAR-T cancer therapies, while individualized, are not drugs). But the path forward is not clear, Dr. Yu and his colleagues acknowledged.

. . .

. . . how might a custom drug’s efficacy might be evaluated, and how should regulators weigh the urgency of the patient’s situation and the number of patients who could ultimately be treated.

For the full story see:

Gina Kolata. “Drug Designed for One Raises Many Questions.” The New York Times (Tuesday, October 15, 2019 [sic]): D3.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the story has the date Oct. 9, 2019 [sic], and has the title “Scientists Designed a Drug for Just One Patient. Her Name Is Mila.” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Dr. Yu that reports on the personalized drug milasen is:

Kim, Jinkuk, Chunguang Hu, Christelle Moufawad El Achkar, Lauren E. Black, Julie Douville, Austin Larson, Mary K. Pendergast, Sara F. Goldkind, Eunjung A. Lee, Ashley Kuniholm, Aubrie Soucy, Jai Vaze, Nandkishore R. Belur, Kristina Fredriksen, Iva Stojkovska, Alla Tsytsykova, Myriam Armant, Renata L. DiDonato, Jaejoon Choi, Laura Cornelissen, Luis M. Pereira, Erika F. Augustine, Casie A. Genetti, Kira Dies, Brenda Barton, Lucinda Williams, Benjamin D. Goodlett, Bobbie L. Riley, Amy Pasternak, Emily R. Berry, Kelly A. Pflock, Stephen Chu, Chantal Reed, Kimberly Tyndall, Pankaj B. Agrawal, Alan H. Beggs, P. Ellen Grant, David K. Urion, Richard O. Snyder, Susan E. Waisbren, Annapurna Poduri, Peter J. Park, Al Patterson, Alessandra Biffi, Joseph R. Mazzulli, Olaf Bodamer, Charles B. Berde, and Timothy W. Yu. “Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1644-52.

An accompanying editorial commenting on the regulatory challenges raised by personalized drugs like milasen is:

Woodcock, Janet, and Peter Marks. “Drug Regulation in the Era of Individualized Therapies.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1678-80.

Ozempic Profits Poured into Massive Supercomputer Meant to Power AI for Future Drug Development

I think AI is currently being oversold. But I am very ignorant and could be wrong, so I favor a diversity of privately-funded bets on what will work to bring us future breakthrough innovations.

(p. B2) Two of the world’s most important companies are now in a partnership born from the success of their most revolutionary products. The supercomputer was built with technology from Nvidia—and money from the Novo Nordisk Foundation. The charitable organization has become supremely wealthy as the largest shareholder in Novo Nordisk, which means this project was made possible by the breakthrough drugs that have sent the Danish company’s stock price soaring.

To put it another way, it’s the first AI supercomputer funded by Ozempic.

It was named Gefion after the goddess of Norse mythology who turned her sons into oxen so they could plow the land that would become Denmark’s largest island.

. . .

Whatever you call it, Gefion is a beast. It is bigger than a basketball court. It weighs more than 30 tons. It took six months to manufacture and install. It also required an investment of $100 million.

. . .

When it’s fully operational, the AI supercomputer will be available to entrepreneurs, academics and scientists inside companies like Novo Nordisk, which stands to benefit from its help with drug discovery, protein design and digital biology.

For the full commentary see:

Ben Cohen. “It’s a Giant New Supercomputer That Might Transform an Entire Country.” The Wall Street Journal (Saturday, Nov. 2, 2024): B2.

(Note: ellipses added.)

(Note: the online version of the commentary has the date November 1, 2024, and has the title “Science of Success; The Giant Supercomputer Built to Transform an Entire Country—and Paid For by Ozempic.”)

Regulations Slow the Creation and Adoption of Healthcare Breakthroughs

CPR is “cardiopulmonary resuscitation.” ECPR is “extracorporeal CPR.” The ATTEST randomized double-blind clinical trial (RCT) provided dramatic evidence of the efficacy of ECPR. But the INCEPTION RCT seemed to provide equally strong evidence of a lack of efficacy. The key difference is the high level of experience and dedication of those implementing the ATTEST RCT, and the lack of experience, and likely lower dedication of those in the INCEPTION RCT. Dr. Demetris Yannopoulos has improved his techniques through trial and error, probably in some ways that he can articulate and in other ways that are harder to articulate. Gary Klein with his naturalistic decision-making research, writes that experience gives emergency workers a quick “recognition” of what needs to be done in different situations.

At what point in the development of a therapy do you perform the canonical RCT? In the case of Emil Freireich’s four drug chemo-cocktail for curing childhood leukemia, he continually improved the ingredients and doses of the cocktail. If an RCT had been performed too early in that process, the result would have been a lack of efficacy, and a therapy would have been abandoned that had the potential to be developed into a useful efficacious therapy. Ditto for Vince DeVita’s development of his chemo-cocktail for curing Hodgkin’s Lymphoma. Ditto also for the development of the drug that eventually proved efficacious in the For Blood and Money book, where Stanford cancer doctor and Pharmacyclics co-founder acquired and developed cancer therapy Imbruvica, but abandoned it after an RCT of it failed. But Miller was ousted by major Pharmacyclics stock-holder, and entrepreneurial non-scientist, Bob Duggan, who did not want to give up on Imbruvica. Duggan persevered, overseeing its further development, until a later RCT was performed that proved efficacy.

In an earlier entry, I documented a much simpler and cheaper CPR innovation that also promises to improve heart failure therapy, called “neuroprotective CPR” (NCPR). Which one, if either, of ECPR or NCPR should we endorse? Ideally, in a fully function medical marketplace, we could comfortably say: “let the market decide.” Entrepreneurial scientists and physicians could develop the therapies and see how many willing patients would be willing to pay for each. Maybe the more expensive ECPR therapy would initially only be bought by the better-off. But as Yannopoulos improves it, as he is already working to do, making it simpler and cheaper, it would eventually be appealing to a broader customers. In Openness, I claim that this is the common path of a great many breakthrough innovations in areas outside of medicine.

Notice that the ECPR was heavily funded by the Helmsley Trust, a private foundation. This is consistent with my claim that medical innovation benefits from a diversity of funding sources, especially of private funding sources that are more likely to fund a diversity of methods and to take chances with heterodox ideas, partly motivated by private funders’ greater mission-orientation due to having more ‘skin-in-the-game.’

Notice also that Yannopoulos’s implementation of ECPR was constrained by a scarcity of trained personnel. Yannopoulos could not act as a nimble entrepreneur because massive regulations limit nimble entrepreneurship in healthcare. This is especially try on labor market issues where massive labor market regulations pile on top of massive healthcare regulations. Breakthrough innovations are usually implemented by small nimble start-ups. To create Disneyland, Walt Disney created WED Enterprises, instead of try to created it with the large incumbent The Walt Disney Company. Jonathan Bush tried nimble labor market innovation in healthcare, but was stymied by regulations. So in the ECPR case, Yannopoulos had the beds to care for more cardiac arrest patients, but could not fill those rooms because of a lack of trained healthcare workers. He could not simply offer higher pay. He was part of a larger organization where he had limited decision-rights that reduced his nimble control. (On the importance of decision-rights, see Koch 2007.)

(p. 27) In reality, by the time a patient without a pulse arrives in the E.R., we know what the outcome is going to be. We continue CPR and shock the patient if we can. We insert a breathing tube and connect it to a ventilator. We inject medications: adrenaline, heart-rhythm drugs. But these treatments almost always fail.

. . .

Demetris Yannopoulos, an interventional cardiologist and professor at the University of Minnesota Medical School who created its Center for Resuscitation Medicine, refused to accept that this was the best doctors could do. In 2014, he began performing ECPR, a treatment that was starting to catch on in a few places, mostly in Asia and Europe. To his surprise, patients he didn’t expect to survive ended up doing well.  . . .

When a patient in cardiac arrest is placed on an extracorporeal membrane oxygenation (ECMO) machine, as Sauer was, the treatment is called ECPR. The type of ECMO intervention used in ECPR provides full life support, which means it does the work of both lungs and heart. (Another type of ECMO, used on Covid-19 patients, helps just with breathing.) ECMO evolved from the heart-lung machines that started being used during heart surgery in the 1950s.

. . .

ECPR by itself doesn’t actually cure anything. But by providing fresh blood flow to the brain and other organs, it lets the body rest and gives doctors time to fix the underlying problem, if it’s fixable.  . . .  After patients are hooked up to ECMO, angiograms of their hearts are typically performed to determine whether they have clogged arteries — as about 85 percent do. In Sauer’s case, Yannopoulos found a blockage in his largest heart vessel, the left anterior descending artery, also known as “the widow maker.” He inserted a stent to open it back up.

. . .

(p. 28) Several years after the program started, Yannopoulos, Bartos and their team conducted the first randomized, controlled trial of ECPR. The results were published in The Lancet in 2020 as the ARREST trial.  . . .

After enrolling just 30 patients, the ARREST trial was stopped early by an N.I.H. board because the patients who got ECPR did so much better than the control-group subjects who received standard resuscitation, and it would have been unethical to continue the study. After six months, 43 percent of the 14 patients who got ECPR were alive with good brain function, compared with zero in the control group.

. . .

The Helmsley Trust gave Yannopoulos grants totaling $19.4 million, which enabled him to add this “hub and spoke” mobile component to his program: The university hospital would be the hub, and a truck and some local hospitals would be the spokes. “It was a real big bet,” Panzirer told me.

To reach patients in areas that were more suburban and rural, Yannopoulos first had to team up with surrounding health systems. Competition is more often the norm among health systems, rather than collaboration, but he persuaded his chief executive, James Hereford, to gather his counterparts from other institutions. Eventually, they were willing to work together. But they had to sort out a lot more than simply agreeing to collaborate. How would insurers pay for what they were doing? Would the initial hospital get the money, or would the university hospital? Would malpractice coverage protect doctors outside their own institutions? What about transport?

Every question could be turned into a reason for hospital administrators and lawyers to say no.

. . .

(p. 29) The economics of ECPR are in line with those of other established lifesaving interventions, like dialysis and heart transplants. And if patients don’t survive, ECPR may perfuse their bodies with enough oxygen to keep their organs eligible for donation. The program in Minnesota costs about $3.2 million a year to operate, which is covered by its revenue. This doesn’t include the start-up funding from the Helmsley Trust, however, or the significant groundwork Yannopoulos laid before that — or his personal sacrifices. “When I started, I had hair and my beard was black,” says Yannopoulos, who is mostly bald and gray. For seven years, he was not paid for his ECPR work; some years, he was on call every day. Today, he still spends about 6,500 hours on call annually. “It’s the force of his will more than anything,” Hereford says when explaining why the program has succeeded.

. . .

Yannopoulos has invited physicians from all over to visit his program; afterward, he often hears from them that replicating his work at their home institutions — getting health and E.M.S. systems to collaborate, finding institutional support and start-up funding, coordinating 24/7 staffing — seems too daunting. For these reasons, Yannopoulos regards his ECPR program as “an administrative and political achievement, rather than a scientific or technological one.”

. . .

(p. 30) The trial, called INCEPTION, compared ECPR with standard care across 10 medical centers in the Netherlands. It was the first randomized, controlled trial to look at ECPR across multiple facilities, and unlike the ARREST trial, it found that ECPR resulted in similar survival as standard treatments.  . . .

Yet there are reasons to interpret the study as saying more about the real-world challenges of developing and implementing ECPR programs than it does about the treatment itself. In the INCEPTION trial, it took roughly a half-hour longer for patients to get on an ECMO machine once they arrived at the hospital than it did in the ARREST study. Of the patients who got ECPR, 12 percent were not successfully connected to the machines, compared with zero in ARREST. Several Dutch hospitals handled only a couple of ECPR cases a year, which means they hadn’t yet acquired the right skills. “I think they were destined for failure because of that rollout, with no experience up front,” Bartos says.

Experience matters profoundly: According to a 2022 paper based on data from the Extracorporeal Life Support Organization, an international nonprofit that Robert Bartlett founded, patients treated at centers that perform fewer than 10 ECPR procedures yearly have 64 percent lower odds of survival; for every 10-case increase, the odds go up 11 percent. (The Minnesota program treats about 150 every year.)

Not only does the procedure itself require mastery, but so, too, does the care in the I.C.U. afterward — an ineffable art as much as a precise science.

. . .

(p. 45) . . . it’s not much of a surprise to hear Yannopoulos ask, “What does INCEPTION have to do with what we’re doing?” His program was carefully developed, with deep expertise, over years, to achieve the best outcomes; INCEPTION studied what would happen if a lot of hospitals started doing ECPR tomorrow.

Engineering the ideal ECPR program can feel like a maddening calculus involving experience, availability and distance — all to beat time. To treat patients faster, maybe doctors should go directly to the scene. For more than a decade, doctors in France have been doing just that, performing ECPR on the streets of Paris, in Métro stations, even on the oak parquet floors of the Louvre. Early on, Lionel Lamhaut, the head of Paris’s ECMO team, was told that he was “a cowboy to try to do something outside the hospital.” But as he and his colleagues persisted, they “started a new way of thinking.”

. . .

. . . as much money as the Helmsley Trust has given, it is not enough to overcome some of the structural limitations in the American health care system. The organization funded a multimillion-dollar expansion of the cardiovascular I.C.U. at Yannopoulos’s hospital to add 12 more spacious rooms specifically designed to accommodate patients on ECMO. But on a weekend in January when I visited, the I.C.U. was closed to new ECPR patients: Not enough nurses were available to work, so four beds in the unit were kept empty.

Even as Yannopoulos and his team hit administrative roadblocks like these, they are still trying to redefine what is medically possible. Recently, a 74-year-old man collapsed on the streets of St. Paul and went into cardiac arrest. Forty-two minutes after the first 911 call, the man was already on ECMO and had regained his pulse. Yannopoulos was optimistic about the case, given how quickly ECMO was started, even though the patient had not been shocked with a defibrillator — which meant he technically fell outside the protocol and should not have received ECPR at all. (After a week in the I.C.U., the man died when his family decided to stop all treatment.)

The man’s heart was almost certainly in pulseless electrical activity (P.E.A.), which many experts think should not be treated with ECPR. Of the three published ECPR randomized, controlled trials, only one did not limit the intervention to people with shockable rhythms. That ambitious trial, in Prague, included patients whose hearts were in the same P.E.A. pattern as the St. Paul man’s. The study was stopped early when it appeared that ECPR wasn’t saving significantly more people than standard care was. These enigmatic cases that lack shockable rhythms are vexing: When the Prague data was reanalyzed without these patients, the findings were favorable for ECPR.

Yannopoulos is undeterred by the Prague results. “You have to decide what’s more important: your survival rate” — what is often used in studies and by institutions to justify support for a program — “or the number of patients you actually save.” Because its program is now well established, Yannopoulos’s team is starting to treat patients with less promising rhythms, even though that may drive down its overall survival rate.  . . .

Yannopoulos wonders if, in a decade or perhaps less, ECPR science will still require the same specially trained teams using the same high-tech equipment — at least before patients get to the hospital. Instead, he imagines small cannulas that will be easy to place in the patient’s neck and attached to compact, simple machines that provide some blood flow to the brain. In his vision, which he is currently working to realize, medics could be trained to start people on this, and then doctors could transition them to regular ECMO once they reach the hospital. If the brain is protected, the rest of the body can eventually recover.

. . .

“There is this idea that people in cardiac arrest, you cannot harm them,” Yannopoulos says. For some doctors, that means cycling relentlessly through chest compressions and medications, so they feel as if they did everything they could. For others, it means briefly going through the motions, so they feel as if they did something. And for still others, it has always seemed kindest to do nothing at all, to let their patients die peacefully. Because almost none of them lived — no matter what the doctors did. “But now we know what is possible,” Yannopoulos says. “So if you’re not achieving that, then you are harming them in a way, right?”

For the full story see:

Helen Ouyang. “Reinventing CPR.” The New York Times Magazine (Sunday, March 31, 2024): 22-31 & 45.

(Note: ellipses added.)

(Note: the online version of the story was updated June [sic] 19, 2024, and has the title “The Race to Reinvent CPR.”)

Some references relevant to my discussion at the start of this entry are:

Bush, Jonathan, and Stephen Baker. Where Does It Hurt?: An Entrepreneur’s Guide to Fixing Health Care. New York: Portfolio, 2014.

DeVita, Vincent T., and Elizabeth DeVita-Raeburn. The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable–and How We Can Get There. New York: Sarah Crichton Books, 2015.

Diamond, Arthur M., Jr. Openness to Creative Destruction: Sustaining Innovative Dynamism. New York: Oxford University Press, 2019.

Klein, Gary A. Seeing What Others Don’t: The Remarkable Ways We Gain Insights. Philadelphia, PA: PublicAffairs, 2013.

Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.

Klein, Gary A. Streetlights and Shadows: Searching for the Keys to Adaptive Decision Making. Cambridge, MA: The MIT Press, 2009.

Koch, Charles G. The Science of Success: How Market-Based Management Built the World’s Largest Private Company. Hoboken, NJ: Wiley & Sons, Inc., 2007.

Silberner, Joanne. “How a Plunger Improved CPR.” The New York Times (Tues., June 27, 2023): D5.

Taleb, Nassim Nicholas. Skin in the Game: Hidden Asymmetries in Daily Life. New York: Random House, 2018.

Vardi, Nathan. For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug. New York: W. W. Norton & Company, 2023.

Starlink Gives Remote Tribes Voice, Information, and Fast Help in Emergencies

(p. 12) . . . Starlink, . . . has quickly dominated the satellite-internet market worldwide by providing service once unthinkable in . . . remote areas. SpaceX has done so by launching 6,000 low-orbiting Starlink satellites — roughly 60 percent of all active spacecraft — to deliver speeds faster than many home internet connections to just about anywhere on Earth, including the Sahara, the Mongolian grasslands and tiny Pacific islands.

Business is soaring. Mr. Musk recently announced that Starlink had surpassed three million customers across 99 countries. Analysts estimate that annual sales are up roughly 80 percent from last year, to about $6.6 billion.

. . .

. . . perhaps Starlink’s most transformative effect is in areas once largely out of the internet’s reach, like the Amazon. There are now 66,000 active contracts in the Brazilian Amazon, touching 93 percent of the region’s legal municipalities. That has opened new job and education opportunities for those who live in the forest. It has also given illegal loggers and miners in the Amazon a new tool to communicate and evade authorities.

One Marubo leader, Enoque Marubo (all Marubo use the same surname), 40, said he immediately saw Starlink’s potential. After spending years outside the forest, he said he believed the internet could give his people new autonomy. With it, they could communicate better, inform themselves and tell their own stories.

Last year, he and a Brazilian activist recorded a 50-second video seeking help getting Starlink from potential benefactors. He wore his traditional Marubo headdress and sat in the maloca. A toddler wearing a necklace of animal teeth sat nearby.

They sent it off. Days later, they heard back from a woman in Oklahoma.

. . .

Allyson Reneau’s LinkedIn page describes her as a space consultant, keynote speaker, author, pilot, equestrian, humanitarian, chief executive, board director and mother of 11 biological children. In person, she says she makes most of her money coaching gymnastics and renting houses near Norman, Okla.

. . .

Enoque was asking for 20 Starlink antennas, which would cost roughly $15,000, to transform life for his tribe.

. . .

[Allyson Reneau said] “One tool would change everything in their life. Health care, education, communication, protection of the forest.”

Ms. Reneau said she bought the antennas with her own money and donations from her children.

. . .

The internet was an immediate sensation.

. . .

They spend lots of time on WhatsApp. There, leaders coordinate between villages and alert the authorities to health issues and environmental destruction. Marubo teachers share lessons with students in different villages. And everyone is in much closer contact with faraway family and friends.

To Enoque, the biggest benefit has been in emergencies. A venomous snake bite can require swift rescue by helicopter. Before the internet, the Marubo used amateur radio, relaying a message between several villages to reach the authorities. The internet made such calls instantaneous. “It’s already saved lives,” he said.

For the full story see:

Jack Nicas and Victor Moriyama. “The Internet’s Final Frontier: Remote Amazon Tribes of Brazil.” The New York Times, First Section (Sunday, June 2, 2024): 1 & 12-13.

(Note: ellipses, and bracketed words, added.)

(Note: the online version of the story was updated June 21 [sic], 2024, and has the title “The Internet’s Final Frontier: Remote Amazon Tribes.”)

The Joy of the Smell Test

If actionable knowledge can come for several sources, but we forbid action based on some of those sources, we will limit our effective action. In the case of health, unnecessary suffering and death will result. In previous entries I highlighted cases where dogs’ advanced ability to smell can diagnose and warn of human maladies more accurately, quicker, and cheaper than other methods. Dog-detectable maladies include Covid, epileptic seizures, and cancer. But the medical establishment underuses this source of knowledge because it is not viewed as scientifically respectable. (And perhaps also because those who practice scientifically respectable ways of knowing, benefit from limiting competition?) The passages quoted below sketch the story of a “hyperosmic” nurse who can smell a distinct odor that identifies those who have and who will have Parkinson’s. Note that follow-up research on this outside-the-box diagnostic method was not funded by governments or universities but by a private foundation founded and funded by Parkinson’s patients and their families and friends. Having a terrible disease sometimes leads to despair, sometimes to a sense of urgency.

(p. 30) As a boy, Les Milne carried an air of triumph about him, and an air of sorrow.  . . .  “We were very, very much in love,” Joy, now a flaxen-haired 72-year-old grandmother, told me recently. In a somewhat less conventional way, she also adored the way Les smelled, and this aroma of salt and musk, accented with a suggestion of leather from the carbolic soap he used at the pool, formed for her a lasting sense of who he was. “It was just him,” Joy said, a steadfast marker of his identity, no less distinctive than his face, his voice, his particular quality of mind.

Joy’s had always been an unusually sensitive nose, the inheritance, she believes, of her maternal line. Her grandmother was a “hyperosmic,” and she encouraged Joy, as a child, to make the most of her abilities, quizzing her on different varieties of rose, teaching her to distinguish the scent of the petals from the scent of the leaves from the scent of the pistils and stamens. Still, her grandmother did not think odor of any kind to be a polite topic of conversation, and however rich and enjoyable and dense with information the olfactory world might be, she urged her granddaughter to keep her experience of it to herself.

. . .

Les spent long hours in the surgical theater, which in Macclesfield had little in the way of ventilation, and Joy typically found that he came home smelling of anesthetics, antiseptics and blood. But he returned one August evening in 1982, shortly after his 32nd birthday, smelling of something new and distinctly unsavory, of some thick must. From then on, the odor never ceased, though neither Les nor almost anyone but his wife could detect it.  . . .

Les had lately begun to change in other ways, however, and soon the smell came to seem almost trivial. It was as if his personality had shifted. Les had rather suddenly become detached, ill-tempered, apathetic. He ceased helping out with many household chores; he snapped at his boys.

. . .

When he began referring to “the other person,” a shadow off to his side, she suspected a brain tumor. Eventually she prevailed upon him to see his doctor, who referred him to a neurologist in Manchester.

Parkinson’s disease is typically classed as a movement disorder, and its most familiar symptoms — tremor, rigidity, a slowing known as bradykinesia — are indeed motoric. But the disease’s autonomic, psychological and cognitive symptoms are no less terrible and commonly begin during the so-called prodrome, years before any changes in movement.

. . .

(p. 31) Feeling desperate, Joy eventually persuaded Les to go with her to a meeting of local Parkinson’s patients and their caregivers.

The room was half full by the time they arrived. Near the coat stand, Joy squeezed behind a man just as he was taking off his jacket and suddenly felt a twitch in her neck, as if some fight-or-flight instinct had been activated, and she raised her nostrils instinctively to the air. She often had this reaction to strong, unexpected scents. In this case, bizarrely, it was the disagreeable odor that had hung about her husband for the past 25 years. The man smelled just like him, Joy realized. So too did all the other patients. The implications struck her immediately.

For nearly all the recorded history of medicine and until only quite recently, smell was a central preoccupation. The “miasma” theory of disease, predominant until the end of the 19th century, held that illnesses of all kinds were spread by noxious odors. By a similar token, particular scents were understood to be curative or prophylactic. More than anything, however, odor was a tool of diagnosis.

The ancients of Greece and China confirmed tuberculosis by tossing a patient’s sputum onto hot coals and smelling the fumes. Typhoid fever has long been known to smell of baking bread; yellow fever smells of raw meat. The metabolic disorder phenylketonuria was discovered by way of the musty smell it leaves in urine, while fish-odor syndrome, or trimethylaminuria, is named for its scent.

. . .

(p. 33) Most diseases can be identified by methods more precise and ostensibly scientific than aroma, however, and we tend to treat odor in general as a sort of taboo. “A venerable intellectual tradition has associated olfaction with the primitive and the childish,” writes Mark Jenner, a professor of history at the University of York. Modern doctors are trained to diagnose by inspection, palpation, percussion and auscultation; “inhalation” is not on the list, and social norms would discourage it if it were.

During her time as a nurse, Joy had done it anyway, reflexively, and learned to detect the acetone breath that signaled an impending diabetic episode, the wet brown cardboard aroma of tuberculosis — “not wet white cardboard, because wet white cardboard smells completely different,” she explained — or the rancidness of leukemia. The notion that Parkinson’s might have a distinctive scent of its own had not occurred to her then, but when it did occur to her years later, it was hardly exotic.

She and Les worried that the normosmics of the world, unfamiliar with medical smells and disinclined to talk about odor in general, might not take her discovery very seriously. They searched for an open-minded scientist and after several weeks settled on Kunath, the Parkinson’s researcher at the University of Edinburgh. In 2012, Joy attended a public talk he gave. During the question-and-answer session, she stood to ask, “Do people with Parkinson’s smell different?” Kunath recalls. “I said, ‘Do you mean, Do people with Parkinson’s lose their sense of smell?’” (Smell loss is in fact a common early symptom of the disease.) “And she said: ‘No, no, no. I mean, Do they smell different?’ And I was just like, ‘Uh, no.’” Joy went home. Kunath returned to his usual work.

Six months later, however, at the urging of a colleague who had once been impressed by cancer-sniffing dogs, Kunath found Joy’s name and called her. She told him the story of Les’s new smell. “I think if she’d told me that, as he got Parkinson’s, he had a change in smell, or if it came afterwards, I probably wouldn’t have followed up any more,” Kunath told me. “But it’s this idea that it was years before.”

He called Perdita Barran, an analytical chemist, to ask what she made of Joy’s claims. Barran suspected Joy was simply smelling the usual odor of the elderly and infirm and misattributing it to Parkinson’s. “I knew, because we all know, that old people are more smelly than young people,” says Barran, who is now a professor of mass spectrometry at the University of Manchester. Still, Barran was personally acquainted with the oddities of olfaction. Following a bike accident, she had for several years experienced various bizarre distortions to her own sense of smell. The idea that Joy might be capable of experiencing odors that no one else could did not strike her as entirely outlandish.

She and Kunath ran a small pilot study in Edinburgh. Through Parkinson’s UK, they recruited 12 participants: six local Parkinson’s patients and six healthy controls. Each participant was asked to wear a freshly laundered T-shirt for 24 hours. The worn shirts were then cut in half down the center, and each half was placed in its own sealed plastic bag. Kunath oversaw the testing. Joy smelled the T-shirt halves at random and rated the intensity of their Parkinsonian odor. “She would find a positive one, and would say, ‘There — it’s right there. Can you not smell it?’” Kunath recalled. Neither he nor the graduate student assisting him could smell a thing.

Kunath unblinded the results at the end of the day. “We were on a little bit of a high,” he recalled. Not only had Joy correctly identified each sample belonging to a Parkinson’s patient, but she was also able, by smell, to match each sample half to its partner. Barran’s skepticism evaporated. Still, Joy’s record was not perfect. She had incorrectly identified one of the controls as a Parkinson’s patient. The researchers wondered if the sample had been contaminated, or if Joy’s nose had simply gotten tired. By Barran’s recollection, Kunath’s response was: “It’s fine! It’s one false positive!” Barran herself was slightly more cautious: Joy had mislabeled both halves of the man’s T-shirt.

Of more immediate interest, though, was the question of what was causing the smell in the first place. The odor seemed to be concentrated not in the armpits, as the researchers had anticipated, but at the neckline. It took them several weeks to realize that it perhaps came from sebum, the lipid-rich substance secreted by the skin. Sebum is among the least studied biological substances. “It is actually another waste disposal for our system,” Barran says. “But no one had ever thought that this was a bodily fluid we could use to find out about disease.”

Barran set out to analyze the sebum of Parkinson’s patients, hoping to identify the particular molecules responsible for the smell Joy detected: a chemical signature of the disease, one that could be detected by machine and could thus form the basis of a universal diagnostic test, a test that ultimately would not depend on Joy’s or anyone else’s nose. No one seemed to be interested in funding the work, though. There were no established protocols for working with sebum, and grant reviewers were unimpressed by the tiny pilot study. They also appeared to find the notion of studying a grandmother’s unusual olfactory abilities to be faintly ridiculous. The response was effectively, “Oh, this isn’t science — science is about measuring things in the blood,” Barran says.

Barran turned to other projects. After nearly a year, however, at a Parkinson’s event in Edinburgh, a familiar-looking man approached Kunath. He had served as one of the healthy controls in the pilot study. “You’re going to have to put me in the other category,” he said, according to Kunath. The man had recently been diagnosed with Parkinson’s. Kunath was stunned. Joy’s “misidentification” had not been an error, but rather an act of clairvoyance. She had diagnosed the man before medicine could do so.

Funding for a full study of Joy, the smell and its chemical components now came through. “We saw something in the news, and we thought, Wow, we’ve got to act on that!” says Samantha Hutten, the director of translational research at the Michael J. Fox Foundation. “The N.I.H. is not going to fund that. Who’s going to fund it if not us?”

. . .

(p. 51) Joy has enjoyed her fame, but the smell work also radicalized her, in its way, and she has a reputation for being a bit intransigent in her advocacy. The initial scientific skepticism toward her was of a piece, she thought, with what she already held to be the medical corps’s hopeless wrongheadedness about Parkinson’s disease. For Joy, as for many caregivers, the psychological aspects of the illness were by far the most difficult to manage, much less accept, and these happened to be precisely the symptoms neurologists seemed least interested in acknowledging, let alone addressing.  . . .

To Joy’s mind, still more proof of this medical obstinacy came from the discovery that she was not alone in her ability to smell Parkinson’s disease. When the research first began to attract attention in the media, Barran and Kunath received messages from around the world from people reporting that they, too, had noticed a change in the smell of their loved ones with Parkinson’s.
  . . .  But for the smell taboo, Joy thought, someone somewhere might have taken these people seriously, and the importance of the odor might have been realized decades sooner.

For the full story see:

Scott Sayare. “The Smell Test.” The New York Times Magazine (Sunday, June 16, 2024): 28-33, 51 & 53.

(Note: ellipses added; bold in original.)

(Note: the online version of the story has the date June 3, 2024, and has the title “The Woman Who Could Smell Parkinson’s.”)

After Safe Drinking Water, Vaccines Were the Second “Most Successful Medical Interventions of the 20th Century”

(p. B11) Dr. Paul D. Parkman, whose research was instrumental in identifying the virus that causes rubella and developing a vaccine that has prevented an epidemic of the disease in the United States for more than 50 years, died on May 7 [2024] at his home in Auburn, N.Y., in the Finger Lakes region. He was 91.

. . .

In 1966, Dr. Parkman, Dr. Harry M. Meyer Jr. and their collaborators at the National Institutes of Health, including Maurice R. Hilleman, disclosed that they had perfected a vaccine to prevent rubella. Dr. Parkman and Dr. Meyer assigned their patents to the N.I.H. so that the vaccines could be manufactured, distributed and administered promptly.

“I never made a nickel from those patents because we wanted them to be freely available to everybody,” he said in an oral history interview for the N.I.H. in 2005.

President Lyndon B. Johnson thanked the researchers, noting that they were among the few who could “number themselves among those who directly and measurably advance human welfare, save precious lives, and bring new hope to the world.”

Still, after Dr. Parkman retired from the government in 1990, as director of the Food and Drug Administration’s Center for Biologics Evaluation and Research, he expressed concern about what he called the unfounded skepticism that persisted about the value of vaccines.

“With the exception of safe drinking water, vaccines have been the most successful medical interventions of the 20th century,” he wrote in 2002 in Food and Drug Administration Consumer, an agency journal.

For the full obituary see:

Sam Roberts. “Paul D. Parkman, 91, Researcher Whose Work Helped to Eliminate Rubella.” The New York Times (Friday, May 24, 2024): B11.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the obituary has the date May 21, 2024, and has the title “Dr. Paul Parkman, Who Helped to Eliminate Rubella, Dies at 91.”)

The 2002 article by Parkman mentioned above is:

Parkman, Paul D. “We Can’t Forget the Value of Vaccines.” Food and Drug Administration Consumer 36, no. 4 (July-Aug. 2002): 40.

Britain’s Socialized National Health Service (NHS) Stripped Parents of Control, Leaving Indi No Choice but to Die

(p. A13) Indi was born with mitochondrial disease, a degenerative condition that prevents cells from producing energy. When her parents and the Queen’s Medical Centre in Nottingham, England, disagreed over whether she should be kept on life support, the NHS turned to the courts to strip the parents of decision-making authority. The U.K. High Court agreed, overrode the parents’ wishes, and ordered life support removed.

. . .

While the NHS thought continued treatment would be futile, other experts disagreed, including at the Vatican’s Bambino Gesù pediatric hospital. As part of its religious mission, Bambino Gesù specializes in treating children with rare diseases. Doctors there offered a treatment plan they thought could help Indi, free of charge. The Italian government even made her a citizen so that she could be airlifted from England.

. . .

For the U.K., the offer of free treatment by willing doctors ought to have been the end of the story. The government didn’t have to pay another penny. The grateful parents simply wanted the freedom to take their daughter to the experts in Rome.

Instead, the NHS went back to the same court and judge to insist it remained in Indi’s best interests to die in the U.K. The court again agreed and overrode the parents’ desire to take Indi to see the experts in Rome. The judge ordered that they could take her only to one place: to the hospice to die.

The parents had no choice but to comply. Lest they try anything else to save their daughter, the parents were sent to hospice with a security escort and police presence.

Deprived of treatment and with her parents forbidden to help her, Indi died within two days, under the watchful eye of the government that said all along it was looking out for her best interests.

For the full commentary, see:

Mark Rienzi. “Britain’s NHS Left Indi Gregory to Die.” The Wall Street Journal (Tuesday, Nov. 21, 2023): A13.

(Note: ellipses added.)

(Note: the online version of the commentary has the date November 20, 2023, and has the same title as the print version.)

FTX Fraudster Sam Bankman-Fried Gave “More Than $5 Million” to Biden’s Winning 2020 Presidential Campaign

Bankman-Fried was convicted of fraud on November 2, 2023.

(p. B4) On the same day that Sam Bankman-Fried’s trial on federal fraud charges begins, the best-selling author Michael Lewis is set to publish a widely anticipated book on Tuesday [Oct. 3, 2023] about Mr. Bankman-Fried’s failed cryptocurrency exchange, FTX.

Mr. Lewis, the author of “The Blind Side,” “The Big Short” and “Moneyball,” spent months interviewing Mr. Bankman-Fried and other top FTX executives, and had access to the company’s headquarters in the Bahamas for the book, “Going Infinite.”

The book features previously unreported details about Mr. Bankman-Fried’s empire, from its founding in the Bay Area to its epic collapse in the Bahamas last year. Here are some takeaways.

. . .

Mr. Bankman-Fried started his first company, the hedge fund Alameda Research, alongside Tara Mac Aulay, an Australian mathematician who moved in the same philanthropic circles.  . . .

According to the book, Ms. Mac Aulay grew to consider Mr. Bankman-Fried “dishonest and manipulative,” and other senior figures at Alameda accused him of mismanagement.

. . .

When FTX was thriving, Mr. Bankman-Fried became a prolific political donor, contributing more than $5 million to Joseph R. Biden Jr.’s 2020 presidential election effort.

For the full story, see:

David Yaffe-Bellany. “Takeaways From a New Book on Sam Bankman-Fried.” The New York Times (Tuesday, October 3, 2023): B4.

(Note: ellipses, and bracketed date, added.)

(Note: the online version of the story has the date October 2, 2023, and has the same title as the print version. Where the online version has more detailed wording, the passages quoted above follow the online version.)

The book reporting new details on the FTX debacle is:

Lewis, Michael. Going Infinite: The Rise and Fall of a New Tycoon. New York: W. W. Norton & Company, Inc., 2023.

Philosopher MacAskill’s “Effective Altruism” Was Neither Effective Nor Altruistic

(p. B1) In short order, the extraordinary collapse of the cryptocurrency exchange FTX has vaporized billions of dollars of customer deposits, prompted investigations by law enforcement and destroyed the fortune and reputation of the company’s founder and chief executive, Sam Bankman-Fried.

It has also dealt a significant blow to the corner of philanthropy known as effective altruism, a philosophy that advocates applying data and evidence to doing the most good for the many and that is deeply tied to Mr. Bankman-Fried, one of its leading proponents and donors. Now nonprofits are scrambling to replace millions in grant commitments from Mr. Bankman-Fried’s charitable vehicles, and members of the effective altruism community are asking themselves whether they might have helped burnish his reputation.

“Sam and FTX had a lot of good will — and some of that good will was the result of association with ideas I have spent my career promoting,” the philosopher William MacAskill, a founder of the effective altruism movement who has known Mr. Bankman-Fried since the FTX founder was an undergraduate at M.I.T., wrote on Twitter on Friday (Nov. 11, 2022). “If that good will laundered fraud, I am ashamed.”

Mr. MacAskill was one of five people from the charitable vehicle known as the FTX Future Fund who jointly announced their resignation on Thursday (Nov. 10, 2022).

. . .

(p. B5) Benjamin Soskis, senior research associate in the Center on Nonprofits and Philanthropy at the Urban Institute, said that the issues raised by Mr. Bankman-Fried’s reversal of fortune acted as a “distorted fun-house mirror of a lot of the problems with contemporary philanthropy,” in which very young donors control increasingly enormous fortunes.

. . .

Mr. Bankman-Fried’s fall from grace may have cost effective-altruist causes billions of dollars in future donations.  . . .

His connection to the movement in fact predates the vast fortune he won and lost in the cryptocurrency field. Over lunch a decade ago while he was still in college, Mr. Bankman-Fried told Mr. MacAskill, the philosopher, that he wanted to work on animal-welfare issues. Mr. MacAskill suggested the young man could do more good earning large sums of money and donating the bulk of it to good causes instead.

. . .

A significant share of the grants went to groups focused on building the effective altruist movement rather than organizations working directly on its causes. Many of those groups had ties to Mr. Bankman-Fried’s own team of advisers. The largest single grant listed on the Future Fund website was $15 million to a group called Longview, which according to its website counts the philosopher Mr. MacAskill and the chief executive of the FTX Foundation, Nick Beckstead, among its own advisers.

The second-largest grant, in the amount of $13.9 million, went to the Center for Effective Altruism. Mr. MacAskill was a founder of the center. Both Mr. Beckstead and Mr. MacAskill are on the group’s board of trustees, with Mr. MacAskill serving as the chair of the United Kingdom board and Mr. Beckstead as the chair of the U.S. subsidiary.

For the full story, see:

Nicholas Kulish. “Collapse of FTX Strikes a Philanthropy Movement.” The New York Times (Monday, November 14, 2022): B1 & B5.

(Note: ellipses, and bracketed dates, added.)

(Note: the online version of the story was updated Nov. 14, 2022, and has the title “FTX’s Collapse Casts a Pall on a Philanthropy Movement.”)

“Effective Altruism” Is Woke, Sanctimonious, Fraudulent, and Ineffective

(p. A1) Sam Bankman-Fried said he wanted to prevent nuclear war and stop future pandemics. And he publicly pledged to use his vast and growing wealth to do so.

But the collapse of Mr. Bankman-Fried’s firm, FTX, and the revelations that he mixed FTX’s money with that of its customers, have upended those declared lofty philanthropic goals.

Run by self-described idealists spending the wealth of their billionaire patron to make the world a better place, Mr. Bankman-Fried’s FTX Foundation and its flagship Future Fund touted deep pockets, ambitious goals and fast turnarounds.

Now Mr. Bankman-Fried’s fortune has disappeared, and the self-described philosopher-executives running the organizations have resigned. Grant recipients are scrambling for cash to plug the shortfall and fretting about the provenance of FTX’s largess after the company’s lawyers said this week that a “substantial amount” of assets were missing and possibly stolen.

. . .

(p. A6) Mr. Bankman-Fried often claimed philanthropy was his primary motivation for amassing a fortune. “It’s the thing that matters the most in the end,” he said in an April interview on the “80,000 Hours” podcast.

Mr. Bankman-Fried has said his law-professor parents instilled in him an interest in utilitarianism, the philosophy of trying to do the greatest good for the greatest number of people.

. . .

Will MacAskill, then a philosophy graduate student, pitched Mr. Bankman-Fried on the idea of effective altruism, a way of applying some utilitarian ideas to charitable giving.

. . .

Mr. Bankman-Fried had considered different career paths, he said in the “80,000 Hours” interview, but Mr. MacAskill suggested he could do the most good by making a lot of money and giving it away, a popular idea in the community.

. . .

Future Fund pledged hundreds of grants worth more than $160 million by September [2022], according to its website.  . . .

Its two largest public grants, of $15 million and $13.9 million, were awarded to effective altruism groups where Mr. MacAskill held roles. Mr. MacAskill, now a professor at Oxford University, wasn’t paid for his involvement in those organizations “other than expenses,” a spokeswoman for one of them said.

. . .

Mr. MacAskill distanced himself from FTX as it was crumbling. In a string of tweets, he accused Mr. Bankman-Fried of personal betrayal and abandoning the principles of effective altruism. He was also one of the Future Fund staffers who quit.

Last week, Mr. Bankman-Fried exchanged messages with a writer at Vox, a news organization that Building A Stronger Future had also pledged to fund.

“You were really good at talking about ethics,” she said.

“I had to be,” Mr. Bankman-Fried responded. He went on to explain it as “this dumb game we woke westerners play where we say all the right shiboleths [sic.] and so everyone likes us.”

For the full story, see:

Rachel Louise Ensign and Ben Cohen. “FTX’s Collapse Wiped Out Founder’s Philanthropic Aims.” The Wall Street Journal (Friday, Nov. 25, 2022): A1 & A6.

(Note: ellipses, and bracketed year, added. The bracketed [sic.] is in the original.)

(Note: the online version of the story has the date November 24, 2022, and has the title “Sam Bankman-Fried Said He Would Give Away Billions. Broken Promises Are All That’s Left.”)

Michael Milken Applies “Entrepreneurial Zeal” to Quest to Live Forever

(p. B3) Michael Milken wants to live forever.

. . .

Milken in April [2023] published “Faster Cures,” a book that is part memoir, part a recounting of his efforts to bring the results of medical research to patients more quickly.

. . .

Shortly after his release from prison in 1993, he received a diagnosis of terminal prostate cancer and was told he had 12 to 18 months to live. He survived thanks to a relentless pursuit of the latest treatments and a dramatic change in diet. Longevity is one focus of the Milken Institute.

. . .

While at Berkeley, Milken read a book called “Corporate Bond Quality and Investor Experience” that examined, among other things, yield charts and default rates for bonds issued by railroads, utilities and industrial companies between 1900 and 1943.

The data revealed something surprising, he recounted in “Faster Cures:” While risk and return had always been presumed to be directly correlated, the reality was that the market had historically overestimated the risk of higher-yielding investments. Investors actually got lower returns on a portfolio of high-grade bonds than they did on a portfolio of low-grade ones over time because the higher yields more than made up for the higher level of defaults.

Milken continued his work on high-yield bonds while pursuing an M.B.A. from the University of Pennsylvania’s Wharton School. When he graduated in 1970, he joined the staff of Drexel, where he had previously worked as a consultant.

Bonds issued by Drexel were the primary source of financing for the likes of cable-industry titan Ted Turner, cellular pioneer Craig McCaw, fiber-optic entrepreneur William McGowan and casino magnate Steve Wynn.

“There was an entrepreneurial zeal in that firm that I haven’t seen since,” said Ted Virtue, a Drexel alumnus who now runs private-equity firm MidOcean Partners.

. . .

Milken’s work on prostate cancer has also made him an influential figure in medical research, where he has developed a reputation for being data-driven and impatient with bureaucracy. Every year he hosts a summit for scientists working on prostate cancer.

“Mike looked at the problem of cancer like a business problem to be solved,” said Dr. Karen Knudsen, CEO of the American Cancer Society. “He wasn’t focused on the flashy. He really focused on what is going to make a difference.”

When the Prostate Cancer Foundation lacked the resources to fund a major study Knudsen needed to conduct to advance her research, she said, Milken introduced her to executives from a pharmaceutical company who he thought would be interested in the science. The company ended up funding the study.

For the full story, see:

Miriam Gottfried. “Bond King, Felon, Billionaire Philanthropist.” The Wall Street Journal (Saturday, July 15, 2023): B3.

(Note: ellipses, and bracketed year, added.)

(Note: the online version of the story was updated July 14, 2023, and has the title “Bond King, Felon, Billionaire Philanthropist: The Nine Lives of Michael Milken.”)

Milken’s book on how to cure more diseases faster is:

Milken, Michael. Faster Cures: Accelerating the Future of Health. New York: William Morrow, 2023.