In “An Entrenched Echo Chamber” the Highly Credentialed Slow Progress Toward an Alzheimer’s Cure

Centralized research funding (often centralized by government agencies) reduces the pluralism of ideas and methods that often lead to breakthrough innovations. The story of Alzheimer’s research, quoted below, is a dramatic case-in-point.

A secondary related lesson from the story quoted below is that Dr. Thambisetty, one of the outsiders struggling to make a difference, is trying to evade the enormous costs of mandated phase 3 clinical trials, by only investigating drugs that already have been approved by the FDA for use against other conditions. With his severely limited funding, and the huge costs of mandated phase 3 clinical trials, this may be a shrewd strategy for Thambisetty, but notice that by following it, he will never explore all the as-yet-unapproved chemicals that might include the best magic bullet against Alzheimer’s.)

(p. A25) What if a preposterous failed treatment for Covid-19 — the arthritis drug hydroxychloroquine — could successfully treat another dreaded disease, Alzheimer’s?

Dr. Madhav Thambisetty, a neurologist at the National Institute on Aging, thinks the drug’s suppression of inflammation, commonly associated with neurodegenerative disorders, might provide surprising benefits for dementia.

It’s an intriguing idea. Unfortunately, we won’t know for quite a while, if ever, whether Dr. Thambisetty is right. That’s because unconventional ideas that do not offer fealty to the dominant approach to study and treat Alzheimer’s — what’s known as the amyloid hypothesis — often find themselves starved for funds and scientific mind share.

Such shortsighted rigidity may have slowed progress toward a cure — a tragedy for a disease projected to affect more than 11 million people in the United States by 2040.

. . .

. . ., in 2006, an animal experiment published in the journal Nature identified a specific type of amyloid protein as the first substance found in brain tissue to directly cause symptoms associated with Alzheimer’s. Top scientists called it a breakthrough that provided a key target for treatments. The paper became one of the most cited in the field, and funds to explore similar proteins skyrocketed.

. . .

In 2022, my investigation in Science showed evidence that the famous 2006 experiment that helped push forward the amyloid hypothesis used falsified data. On June 24 [2024], after most of its authors conceded technical images were doctored, the paper was finally retracted.

. . .

In reporting for my forthcoming book about the disturbing state of play in Alzheimer’s research, I’ve spoken to many scientists pursuing alternatives. Dr. Thambisetty, for example, compares brain tissues from people who died in their 30s or 40s with and without genetic risk factors for Alzheimer’s. He then compares these findings to tissues from deceased Alzheimer’s patients and people who didn’t have the disease. Where changes overlap, drug targets might emerge. Rather than develop new drugs through lab and animal testing, followed by clinical trials that cost vast sums — a process that can take decades — he examines treatments already approved as reasonably safe and effective for other conditions. Patent protections have lapsed for many, making them inexpensive.

Experiments have also begun to test the weight-loss drug semaglutide (sold as Wegovy, among other brands). Researchers hope that results due in 2026 will show that its anti-inflammatory effects — like Dr. Thambisetty’s idea about hydroxychloroquine — slow cognitive decline.

Ruth Itzhaki, a research scientist at the University of Oxford, stirred curiosity in the 1990s when she shared evidence tying Alzheimer’s to herpesvirus — a scourge spread by oral or genital contact and often resulting in painful infections. For years, powerful promoters of the amyloid hypothesis ignored or dismissed the infection hypothesis for Alzheimer’s, effectively rendering it invisible, Dr. Itzhaki said with exasperation. Research suggests that viruses may hide undetected in organs, including the brain, for years, causing symptoms divergent from the original infection.

. . .

Sometimes a disease stems from a single clear-cut origin, such as genetic mutations that cause deadly sickle cell disease. “But very few diseases of aging have just one cause. It’s just not logical,” said Dr. Matthew Schrag, a neurologist at Vanderbilt University Medical Center. Working independently of his university, he discovered the 2006 research image manipulations.

. . .

“There is an entrenched echo chamber that involves a lot of big names,” Dr. Schrag said. “It’s time for the field to move on.”

For the full commentary see:

Charles Piller. “All the Alzheimer’s Research We Didn’t Do.” The New York Times (Friday, July 12, 2024): A25.

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

(Note: the online version of the commentary has the date July 7, 2024, and has the same title as the print version. Where there are a couple of small differences in wording, the passages quoted above follow the online version.)

Piller’s paper in Science, mentioned above, is:

Piller, Charles. “Blots on a Field?” Science 377, no. 6604 (July 2022): 358-63.

Piller’s commentary is related to his forthcoming book:

Piller, Charles. Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s. New York: Atria/One Signal Publishers, Forthcoming on February 4, 2025.

A Dollar Spent on Medicaid Yields (at Most) 40 Cents of Value to Recipients

(p. C3) A . . . National Bureau of Economic Research study estimated the value of Medicaid to its recipients at between 20¢ and 40¢ per dollar of expenditure, with the majority of the value going to health-care providers like doctors and hospitals. By comparison, the Earned Income Tax Credit—a cash transfer program designed to enhance the incomes of the working poor—delivers around 90¢ of value to its recipients per dollar of expenditure. Given that more than half of Obamacare’s reduction in the numbers of the uninsured has been from its expansion of Medicaid, this makes the law look more like welfare for the medical-industrial complex than support for the needy.

For the full commentary see:

Daniel P. Kessler. “The Health of Obamacare.” The Wall Street Journal (Saturday, Dec. 12, 2015 [sic]): C3.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date Dec. 11, 2015 [sic], and has the same title as the print version.)

The NBER working paper mentioned above was later published in:

Finkelstein, Amy, Nathaniel Hendren, and Erzo F. P. Luttmer. “The Value of Medicaid: Interpreting Results from the Oregon Health Insurance Experiment.” Journal of Political Economy 127, no. 6 (Dec. 2019): 2836-74.

(Note: my title for this blog entry continues to be supported in the 2019 published version of the earlier NBER working paper.)

Commercial Logging Would Reduce the Size and Number of Canadian Summer Wildfires and Intense Smoke

(p. A4) The loggers’ work was unmistakable.

Flanked by dense forests, the mile-long, 81-acre expanse of land on the mountainside had been stripped nearly clean. Only scattered trees still stood, while some skinny felled trunks had been left behind. A path carved out by logging trucks was visible under a light blanket of snow.

The harvesting of trees would be routine in a commercial forest — but this was in Banff, Canada’s most famous national park. Clear-cutting was once unimaginable in this green jewel in the Canadian Rockies, where the longstanding policy was to strictly suppress every fire and preserve every tree.

But facing a growing threat of wildfires, national park caretakers are increasingly turning to loggers to create fire guards: buffers to stop forest fires from advancing into the rest of the park and nearby towns.

“If you were to get a highly intense, rapidly spreading wildfire, this gives fire managers options,’’ David Tavernini, a fire and vegetation expert at Parks Canada, the federal agency that manages national parks, said as he treaded on the cleared forest’s soft floor.

. . .

Long-planned measures meant to protect against wildfires — like the fire guard in Alberta’s Banff park and other projects in the town of Banff — have taken on a greater sense of urgency.

. . .

The increased number of fires in sparsely populated areas of Canada has affected not only nearby communities, but also distant ones, with the intense smoke they have generated floating into southern Canada and into the United States.

. . .

In Banff National Park, which was created in 1885 and is Canada’s oldest, officials until 1983 hewed to a strict policy of fire suppression, rather than take significant steps to prevent or manage fires.

The result now is a landscape of dense forests dominated by conifers, which are extremely flammable.

Historical photos of the area before the park was established show a greater variety of trees and more open spaces, said Mr. Tavernini, the fire and vegetation expert at Parks Canada. Lightning and controlled burns by the local Indigenous people regularly thinned out the forests, he said.

For the full story see:

Norimitsu Onishi. “In the Canadian Rockies, Logging Parks to Save Them.” The New York Times (Thursday, May 30, 2024): A4.

(Note: ellipses added.)

(Note: the online version of the story has the date May 29, 2024, and has the title “Logging in Canada’s Most Famous National Park to Save It From Wildfires.”)

Gates’s TerraPower Breaks Ground on Small Nuclear Reactor

(p. A16) Outside a small coal town in southwest Wyoming, a multibillion-dollar effort to build the first in a new generation of American nuclear power plants is underway.

Workers began construction on Tuesday on a novel type of nuclear reactor meant to be smaller and cheaper than the hulking reactors of old and designed to produce electricity without the carbon dioxide that is rapidly heating the planet.

The reactor being built by TerraPower, a start-up, won’t be finished until 2030 at the earliest and faces daunting obstacles. The Nuclear Regulatory Commission hasn’t yet approved the design, and the company will have to overcome the inevitable delays and cost overruns that have doomed countless nuclear projects before.

What TerraPower does have, however, is an influential and deep-pocketed founder. Bill Gates, currently ranked as the seventh-richest person in the world, has poured more than $1 billion of his fortune into TerraPower, an amount that he expects to increase.

“If you care about climate, there are many, many locations around the world where nuclear has got to work,” Mr. Gates said during an interview near the project site on Monday. “I’m not involved in TerraPower to make more money. I’m involved in TerraPower because we need to build a lot of these reactors.”

Mr. Gates, the former head of Microsoft, said he believed the best way to solve climate change was through innovations that make clean energy competitive with fossil fuels, a philosophy he described in his 2021 book, “How to Avoid a Climate Disaster.”

Nationwide, nuclear power is seeing a resurgence of interest, with several start-ups jockeying to build a wave of smaller reactors and the Biden administration offering hefty tax credits for new plants.

. . .

In March [2024], TerraPower submitted a 3,300-page application to the Nuclear Regulatory Commission for a permit to build the reactor, but that will take at least two years to review. The company has to persuade regulators that its sodium-cooled reactor doesn’t need many of the costly safeguards required for traditional light-water reactors.

“That’s going to be challenging,” said Adam Stein, director of nuclear innovation at the Breakthrough Institute, a pro-nuclear research organization.

TerraPower’s plant is designed so that major components, like the steam turbines that generate electricity and the molten salt battery, are physically separate from the reactor, where fission occurs. The company says those parts don’t require regulatory approval and can begin construction sooner.

For the full story see:

Brad Plumer and Benjamin Rasmussen. “Climate-Minded Billionaire Makes a Bet on Nuclear Power.” The New York Times (Thursday, June 13, 2024): A16.

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

(Note: the online version of the story has the date June 11, 2024, and has the title “Nuclear Power Is Hard. A Climate-Minded Billionaire Wants to Make It Easier.”)

Gates’s 2021 book, mentioned above, is:

Gates, Bill. How to Avoid a Climate Disaster: The Solutions We Have and the Breakthroughs We Need. New York: Knopf, 2021.

With Metformin Patent Expired, No Firm Has Incentive to Fund $50 Million Randomized Clinical Trial to Show It Aids Longevity

The article quoted below was published eight years ago. Dr. Barzilai and his team are still, even now, trying to raise the (probably higher) funds to conduct the metformin clinical trial. Firms have no incentive to conduct the clinical trial. Since the patent for metformin (originally issued for its efficacy against diabetes) expired in the year 2000, even if the clinical trial succeeded, no firm would be able to recover in revenue the $50 cost of conducting the clinical trial. Clinical trials are so hugely expensive largely due to the large and long Phase 3 component, intended to prove efficacy. That is why I salute Milton Friedman’s suggestion that a step in the right direction would be for the FDA to only mandate the smaller and quicker Phase 1 and Phase 2 components, mainly intended to prove safety. If the total cost of the clinical trial was much lower, it might be easier to find non-profit or academic funding. (It’s hard to raise $50 million on a GoFundMe page!)

The system is set up so that cheap (off-patent) drugs like metformin do not get tested, and so do not get FDA approval for off-label uses. So the system is set up to reduce the use of low cost, but possibly effective, medicines.

(p. D5) “Aging is by far the best predictor of whether people will develop a chronic disease like atherosclerotic heart disease, stroke, cancer, dementia or osteoarthritis,” Dr. James L. Kirkland, director of the Kogod Center on Aging at the Mayo Clinic, said in an interview. “Aging way outstrips all other risk factors.”

He and fellow researchers, who call themselves “geroscientists,” are hardly hucksters hawking magic elixirs to extend life. Rather, they are university scientists joined together by the American Federation for Aging Research to promote a new approach to healthier aging, which may — or may not — be accompanied by a longer life. They plan to test one or more substances that have already been studied in animals, and which show initial promise in people, in hopes of finding one that will keep more of us healthier longer.

As Dr. Kirkland wrote in . . ., “Aging: The Longevity Dividend”: “By targeting fundamental aging processes, it may be possible to delay, prevent, alleviate or treat the major age-related chronic disorders as a group instead of one at a time.”

. . .

The team, which includes Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in The Bronx, and Steven N. Austad, who heads the biology department at the University of Alabama at Birmingham, plans to study one promising compound, a generic drug called metformin already widely used in people with Type 2 diabetes. They will test the drug in a placebo-controlled trial involving 3,000 elderly people to see if it will delay the development or progression of a variety of age-related ailments, including heart disease, cancer and dementia. Their job now is to raise the $50 million or so needed to conduct the study for the five years they expect it will take to determine whether the concept has merit.

. . .

Several studies have . . . found that individuals with exceptional longevity experience a compression of morbidity and spend a smaller percentage of their life being ill, Dr. Barzilai and his colleague Dr. Sofiya Milman wrote in the “Aging” book.

For the full commentary see:

Jane E. Brody. “Pursuing the Dream of Healthy Aging.” The New York Times (Tuesday, February 2, 2016 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the commentary has the date February 1, 2016 [sic], and has the title “Finding a Drug for Healthy Aging.”)

Dr. Kirkland’s co-edited book mentioned above is:

Olshansky, S. Jay, George M. Martin, and James L. Kirkland, eds. Aging: The Longevity Dividend, A Subject Collection from Cold Spring Harbor Perspectives in Medicine. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2015.

One study that documents that those who live 107 or more years do not have more years of illness and morbidity (the “compression of morbidity hypothesis”) is:

Sebastiani, Paola, and Thomas T. Perls. “The Genetics of Extreme Longevity: Lessons from the New England Centenarian Study.” Frontiers in Genetics 3 (Nov. 30, 2012).

The “Silver Linings” of Illegally Trafficked Corals

(p. D4) Corals are not plants: They are tiny invertebrates that live in vast colonies, forming the foundation of the world’s tropical reefs. Marine life traffickers hammer and chisel them off reefs in places like Indonesia, Fiji, Tonga, Australia or the Caribbean, then pack them into small baggies of seawater so they can be boxed up by the hundreds and shipped around the world. While most coral is shipped into the United States legally, individuals and wholesalers, growing in number, are being intercepted with coral species or quantities that are restricted or banned from trade, often hidden inside shipments containing legal species.

. . .

Corals are better left in the wild, experts say, but there are silver linings after illegally trafficked specimens are confiscated and properly cared for by experts. In fact, there’s a good chance you’ve seen a confiscated coral if you’ve visited some aquariums.

Walk past the Indo-Pacific Barrier Reef exhibit at the Georgia Aquarium, for instance, and you can view a Turbinaria coral that was confiscated in 2005, shortly after Ms. Stone joined the aquarium.

It took years for the Turbinaria to recover, but now the colony has grown to more than 2.5 feet in size under her care and taken on a shape like a giant eye.

For the full story see:

Jason Bittel. “Mobilizing a Network to Save Marine Corals.” The New York Times (Tuesday, June 25, 2024): D4.

(Note: ellipsis added.)

(Note: the online version of the story has the date June 24, 2024, and has the title “Unlikely Wild Animals Are Being Smuggled Into U.S. Ports: Corals.”)

Physicians Are Reluctant to Assign Their Patients to a Clinical Trial of a New Therapy That Might Replace the Therapy They Know and Practice

(p. D1) After learning he had early stage prostate cancer, Paul Kolnik knew he wanted that cancer destroyed immediately and with as little disruption as possible to his busy life as the New York City Ballet’s photographer.

So Mr. Kolnik, 65, chose a type of radiation treatment that is raising some eyebrows in the prostate cancer field. It is more intense than standard radiation and takes much less time — five sessions over two weeks instead of 40 sessions over about two months or 28 sessions over five to six weeks.

. . .

The National Cancer Institute has just agreed to fund a clinical trial that researchers hope will settle which treatment is better. It will randomly assign 538 men to have either a short course of five intense radiation sessions over two weeks or 28 treatments over five and a half weeks, comparing outcomes for quality of life as well as disease-free survival.

But it will be at least eight years before the answers are in. In the meantime, men and their doctors are left with uncertainty.

“Ideally, we want to show five treatments (p. D4) is better,” said Dr. Rodney J. Ellis, a radiation oncologist at Case Comprehensive Cancer Center in Cleveland and the principal investigator for the trial.

One reason for the dearth of data is that prostate cancer usually grows slowly, if at all, so it can take many years to see if a treatment saved lives. It is expensive and difficult to follow patients for such a long time, and the treatments given to the men often change over a decade, making doctors wonder if the results are relevant.

Also, researchers who have tried to conduct studies comparing treatments often failed because specialists were already convinced that the method they used was best and were reluctant to assign men to other treatments. Dr. Ian Thompson of the University of Texas Health Science Center in San Antonio, said he was involved with several clinical trials that withered for that reason.

. . .

The researchers on the new study think recruitment will not be a major problem because they are comparing different courses of radiation, rather than entirely different approaches — for example, surgical removal of the prostate versus implantation of radioactive seeds in the prostate. A study to investigate those two approaches closed because investigators were able to enroll only 20 patients, Dr. Thompson said.

. . .

A few years ago, Dr. Yu and his colleagues looked at Medicare data and reported that men who had more intense radiation therapy were more likely to have urinary problems after two years than those who had the longer-course therapy.

Dr. Yu noted that his study was not a randomized trial, the gold standard, but he said the results were not reassuring. Now, though, he is not so sure the intense therapy is worse.

“In my own experience, these men have done really well,” he said. “That tells us that techniques improved, or the medical claims we evaluated were not indicative of major toxicity, or the way we and others at high-volume centers deliver radiotherapy is different.”

The lack of solid data bothers Dr. Daniel W. Lin, chief of urologic oncology at the University of Washington. When men ask him about the shorter radiation course, he tells them, “It probably can work but it doesn’t have long-term results and it hasn’t been tested against standard radiation.”

At centers like Sloan Kettering, doctors are relying on their own experience.

Dr. Michael J. Zelefsky, a radiation oncologist who treated Mr. Kolnik there, said that several years ago, 90 percent of his patients had the standard course of treatment. Now 90 percent choose the shorter course. On the basis of Sloan Kettering’s experience with several hundred men who had the intense radiation therapy over the past three years, the treatment, he said, “is emerging as a very exciting form of therapy.”

For the full story see:

Gina Kolata. “Unproven Therapy Gains Ground.” The New York Times (Tuesday, March 21, 2017 [sic]): D1 & D4.

(Note: ellipses added.)

(Note: the online version of the story has the date March 20, 2017 [sic], and has the title “Popular Prostate Cancer Therapy Is Short, Intense and Unproven.”)

California Politicians Ban Test of Sprayed Seawater That Might Reverse Global Warming

Some environmentalists are only willing to cool the planet by the pain of less consumption.

(p. A14) Elected leaders in Alameda, Calif., voted early on Wednesday [June 5, 2024] to stop scientists from testing a device that might one day be used to artificially cool the planet, overruling city staff members who had found the experiment posed no danger.

. . .

The test involved spraying tiny sea-salt particles across the flight deck of a decommissioned aircraft carrier, the U.S.S. Hornet, docked in Alameda in San Francisco Bay. Versions of that device could eventually be used to spray the material skyward, making clouds brighter so that they reflect more sunlight away from Earth. Scientists say that could help to cool the planet and to fight the effects of global warming.

. . .

“The chemical components of the saltwater solution (which is similar to seawater) being sprayed are naturally occurring in the environment,” the report said. Staff recommended that the City Council allow the experiment to continue, . . .

. . .

Some environmentalists oppose research aimed at so-called climate intervention, also known as solar geoengineering. They argue that such technology carries the risk of unintended consequences, and also takes money and attention away from efforts to reduce the use of fossil fuels, the burning of which is the underlying cause of climate change.

For the full story see:

Soumya Karlamangla and Christopher Flavelle. “Leaders in California City Halt Cloud-Brightening Test.” The New York Times (Thursday, June 6, 2024): A14.

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

(Note: the online version of the story has the date June 5, 2024, and has the title “California City Leaders End Cloud-Brightening Test, Overruling Staff.”)

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.”)

The Dubious Result of a Randomized Controlled Trial (RCT)

Randomized controlled trials are widely viewed as the “gold standard” of medical evidence. But RCTs can be flawed in a variety of ways. They can have too few participants, they can be improperly randomized for a variety of reasons (not all relevant variables may have been identified or the protocol may not have been properly implemented). Forgive me, but the results of the RCT described below seem highly implausible. I believe that something about the RCT was flawed. Who can believe the result that those who engage in moderate exercise live shorter lives than those who only engage in very modest exercise. Common sense and many observational studies say the opposite, and such evidence should not be cavalierly dismissed.

(p. D6) Scientists have known for some time, . . ., that active people tend also to be long-lived people. According to multiple past studies, regular exercise is strongly associated with greater longevity, even if the exercise amounts to only a few minutes a week.

But almost all of these studies have been observational, meaning they looked at people’s lives at a moment in time, determined how much they moved at that point, and later checked to see whether and when they passed away. Such studies can pinpoint associations between exercise and life spans, but they cannot prove that moving actually causes people to live longer, only that activity and longevity are linked.

To find out if exercise directly affects life spans, researchers would have to enroll volunteers in long-term, randomized controlled trials, with some people exercising, while others work out differently or not at all. The researchers then would have to follow all of these people for years, until a sufficiently large number died to allow for statistical comparisons of the groups.

Such studies, however, are dauntingly complicated and expensive, one reason they are rarely done. They may also be limited, since over the course of a typical experiment, few adults may die. This is providential for those who enroll in the study but problematic for the scientists hoping to study mortality; with scant deaths, they cannot tell if exercise is having a meaningful impact on life spans.

Those obstacles did not deter a group of exercise scientists at the Norwegian University of Science and Technology in Trondheim, Norway, however. With colleagues from other institutions, they had been studying the impacts of various types of exercise on heart disease and fitness and felt the obvious next step was to look at longevity. So, almost 10 years ago, they began planning the study that would be published in October [2020] in The BMJ.

. . .

The scientists tested everyone’s current aerobic fitness as well as their subjective feelings about the quality of their lives and then randomly assigned them to one of three groups. The first, as a control, agreed to follow standard activity guidelines and walk or otherwise remain in motion for half an hour most days. (The scientists did not feel they could ethically ask their control group to be sedentary for five years.)

Another group began exercising moderately for longer sessions of 50 minutes twice a week. And the third group started a program of twice-weekly high-intensity interval training, or H.I.I.T., during which they cycled or jogged at a strenuous pace for four minutes, followed by four minutes of rest, with that sequence repeated four times.

. . .

The men and women in the high-intensity-intervals group were about 2 percent less likely to have died than those in the control group, and 3 percent less likely to die than anyone in the longer, moderate-exercise group. People in the moderate group were, in fact, more likely to have passed away than people in the control group.

For the full story see:

Gretchen Reynolds. “Working Out With Intensity.” The New York Times (Tuesday, December 29, 2020 [sic]): D6.

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

(Note: the online version of the story was updated Nov. 10, 2021 [sic–yes 2021], and has the title “The Secret to Longevity? 4-Minute Bursts of Intense Exercise May Help.” Where the wording of the versions slightly differs, the passages quoted above follow the online version.)

The study published in The British Medical Journal (BMJ), and mentioned above, is:

Stensvold, Dorthe, Hallgeir Viken, Sigurd L. Steinshamn, Håvard Dalen, Asbjørn Støylen, Jan P. Loennechen, Line S. Reitlo, Nina Zisko, Fredrik H. Bækkerud, Atefe R. Tari, Silvana B. Sandbakk, Trude Carlsen, Jan E. Ingebrigtsen, Stian Lydersen, Erney Mattsson, Sigmund A. Anderssen, Maria A. Fiatarone Singh, Jeff S. Coombes, Eirik Skogvoll, Lars J. Vatten, Jorunn L. Helbostad, Øivind Rognmo, and Ulrik Wisløff. “Effect of Exercise Training for Five Years on All Cause Mortality in Older Adults—the Generation 100 Study: Randomised Controlled Trial.” BMJ 371 (2020): m3485.

Biden’s Tax and Regulation Plans Shift “Demonized” Silicon Valley Toward Trump

(p. B1) In 2021, David Sacks, a prominent venture capital investor and podcast host, said former President Donald J. Trump’s behavior around the Jan. 6 [2021] riot at the U.S. Capitol had disqualified him from being a future political candidate.

At a tech conference last week, Mr. Sacks said his view had changed.

“I have bigger disagreements with Biden than with Trump,” the investor said. Mr. Sacks said he and his podcast co-hosts were working on hosting a fund-raiser for Mr. Trump, which could include an interview for their “All In” show.  . . .

Such public support for Mr. Trump used to be taboo in Silicon Valley, which has long been seen as a liberal bastion. But frustration with Mr. Biden, Democrats and the state of the world has increasingly driven some of tech’s most prominent venture capitalists to the right.

. . .

(p. B5) Delian Asparouhov, an investor at Founders Fund, the investment firm founded by Mr. Thiel, recently marveled at how much the political winds had shifted. This month, Mr. Trump made a virtual appearance at a venture capital conference in Washington. There, he thanked attendees for “keeping your chin up” and said he looked forward to meeting them.

“Four years ago you had to issue an apology if you voted for him,” Mr. Asparouhov wrote on X.

Mr. Sacks, Mr. Palihapitiya and Founders Fund did not respond to a request for comment. Sequoia Capital declined to comment.

The comments and activity by the group of tech investors are particularly noticeable given Silicon Valley’s blue background.

. . .

The . . . “techlash” against Facebook and others caused some industry leaders to reassess their political views, a trend that continued through the social and political turmoil of the pandemic.

During that time, Democrats moved further to the left and demonized successful people who made a lot of money, further alienating some tech leaders, said Bradley Tusk, a venture capital investor and political strategist who supports Mr. Biden.

“If you keep telling someone over and over that they’re evil, they’re eventually not going to like that,” he said. “I see that in venture capital.”

That feeling has hardened under President Biden. Some investors said they were frustrated that his pick for chair of the Federal Trade Commission, Lina Khan, has aggressively moved to block acquisitions, one of the main ways venture capitalists make money. They said they were also unhappy that Mr. Biden’s pick for head of the Securities and Exchange Commission, Gary Gensler, had been hostile to cryptocurrency companies.

The start-up industry has also been in a downturn since 2022, with higher interest rates sending capital fleeing from risky bets and a dismal market for initial public offerings crimping opportunities for investors to cash in on their valuable investments.

Some also said they disliked Mr. Biden’s proposal in March [2024] to raise taxes, including a 25 percent “billionaire tax” on certain holdings that could include start-up stock, as well as a higher tax rate on profits from successful investments.

Mr. Sacks said at the tech conference last week that he thought such taxes could kill the start-up industry’s system of offering stock options to founders and employees. “It’s a good reason for Silicon Valley to think really hard about who it wants to vote for,” he said.

. . .

Mr. Andreessen, a founder of Andreessen Horowitz, a prominent Silicon Valley venture firm, said in a recent podcast that “there are real issues with the Biden administration.” Under Mr. Trump, he said, the S.E.C. and F.T.C. would be headed by “very different kinds of people.” But a Trump presidency would not necessarily be a “clean win” either, he added.

Last month, Mr. Sacks, Mr. Thiel, Elon Musk and other prominent investors attended an “anti-Biden” dinner in Hollywood, where attendees discussed fund-raising and ways to oppose Democrats, a person familiar with the situation said. The dinner was earlier reported by Puck.

For the full story see:

Erin Griffith. “Silicon Valley Notables Are Shifting to the Right.” The New York Times (Friday, May 24, 2024): B1 & B5.

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

(Note: the online version of the story has the date May 22, 2024, and has the title “Some of Silicon Valley’s Most Prominent Investors Are Turning Against Biden.”)