Health – Page 9 – artdiamondblog.com

Mainstream Approach to Alzheimer’s Is Built on Doctored Data

Widespread fraud among highly credentialled, and richly financed, medical researchers results in fewer and slower cures. Many millions of dollars are required to bring a major drug to market, much of it due to the hyper-costly and mandated Phase 3 randomized double-blind clinical trials. There are more good ideas than can receive such financing. The intense competition creates a temptation to cut various corners, as the book review quoted below emphasizes.

Aaron Rothstein, the reviewer of Piller’s Doctored book, emphasizes the sad revelation of widespread fraud. But in an earlier entry on this blog, I quoted an essay of Piller’s that suggests that Piller also has something substantive to say about how to cure Alzheimer’s. The current system is broken, vastly reducing the diversity of approaches to curing important diseases like Alzheimer’s. Piller suggests that the ruling clique among Alzheimer’s researchers may in effect be silencing other approaches that could bring us a better faster cure.

Rothstein downplays this substantive aspect of Piller’s book. (It probably reflects too much cynicism on my part to wonder how close Rothstein himself is to the ruling clique?)

I look forward to reading Piller’s book, both for what it has to say about widespread fraud and for what it has to say about Alzheimer’s. Doctored is scheduled for release in a few days, on February 4, 2025.

(p. C9) In 2023 my colleagues and I were preparing to enroll patients in a clinical trial of a new drug that promised to mitigate brain damage in stroke victims. The National Institutes of Health, a governmental organization that funds billions of dollars of research every year, had committed $30 million to the trial. The drug was, in part, the brainchild of Berislav Zlokovic, a neuroscientist at the University of Southern California.

Then, suddenly, the NIH paused the trial. Charles Piller, an investigative journalist for Science magazine, had published an article alleging that multiple papers from Dr. Zlokovic, including many supporting the new drug, contained seemingly altered data. Though Dr. Zlokovic disputed some of the concerns, this news stunned us. We might have put patients at risk, while offering groundless hope. A fraud of the sort Mr. Piller described would violate the basic ethics of clinical trials and overturn the presumption of trust on which the practice of medicine relies.

I thought of this episode often as I read Mr. Piller’s “Doctored,” which brings together his long-form journalism about neuroscience-research malfeasance, including that alleged of Dr. Zlokovic. Though the book sometimes attempts to do too much—diving into scientific theories about the causes of Alzheimer’s, for example—its strength lies in Mr. Piller’s dramatic and damning investigation of scientific transgression. The author’s reporting is largely based on the research of Matthew Schrag, a Vanderbilt neurologist who uses technical expertise to identify episodes of misconduct.

. . .

Mr. Piller thoroughly double checks Dr. Schrag’s work. He asks researchers and image analysts to confirm Dr. Schrag’s findings, and they concur.

. . .

“Doctored” demonstrates how some of the most accomplished and elite scientific gatekeepers may have lied, cheated, squandered trust and endangered lives. How did this happen? The temptations of ego and fame perennially entice humans, but our system of peer review, grant funding and administrative oversight is meant to check these temptations.

The scientific publication process does not contain all the safeguards one might expect. Peer reviewers do not always see the original data from authors. Thus they trust that numbers or images in a manuscript accurately reflect the experiment. And determining whether an image is fraudulent requires skilled image analysis that peer reviewers may not possess. Furthermore, digging for such mistakes is costly: It takes time away from other research, from teaching, from seeing patients and from home life.

What can be done about this? Making raw data available to peer reviewers and giving them time to review articles could help. Mr. Piller suggests a less professionally incestuous relationship between researchers, the Food and Drug Administration, the NIH and pharmaceutical companies could reduce favoritism in funding. A major overhaul of the finances and administrative swell of our system would help, as well.

For the full review see:

Aaron Rothstein. “Medical Promise Betrayed.” The Wall Street Journal (Saturday, Jan. 25, 2025): C9.

(Note: the online version of the review has the date January 24, 2025, and has the title “‘Doctored’ Review: Medical Promise Betrayed.”)

The book under review is:

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

Surgeons Respond More to Individual Incentives Than to Group Incentives

Medicare introduced a new billing code that reimburses surgeons more for repairing hernias that are at least 3 cm long. As a result the percent of repaired hernias that were less than 3 cm dropped from 60% to 49%. It is probably not too hard for surgeons to justify this change. Probably surgeries on hernias just under 3 cm, are just as hard to do as surgeries on hernias that are just above 3 cm. So probably it seems arbitrarily unfair to reimburse more for the slightly larger ones. So look at the close calls closer until you find an angle where one that on first glance was less than 3 cm, now appears to be more than 3 cm.

On the other hand, consider the response when Blue Cross Blue Shield in Michigan offered to pay more to urology group practices that had more patients on active surveillance for prostate cancer. (A growing consensus suggests that most low-risk prostate cancer patients would be better off with active surveillance, rather than quick prostate surgery by urologists.) The response by Michigan urologists–no change in the percent of prostate cancer patients on active surveillance.

Why the difference? I suggest that surgeons, like other people, respond more to individual incentives than to group incentives. A person who responds to group incentives bears the costs themselves, but shares the benefits with others who may be free-riders. If the incentive is individual, no one free rides.

I became aware of the recent academic articles on how incentives do or don’t influence surgeons by reading:

Millenson, Michael L. “It’s Money That Changes Everything (or Doesn’t) for Surgeons.” Forbes.com, Jan. 26, 2025 [cited Jan 27, 2025]. Available from https://www.forbes.com/sites/michaelmillenson/2025/01/26/its-money-that-changes-everything-or-doesnt-for-surgeons/ .

The academic article showing that individual incentives matter to some surgeons is:

Hallway, Alexander, Erin Isenberg, Ryan Howard, Sean O’Neill, Jenny Shao, Leah Schoel, Michael Rubyan, Anne Ehlers, and Dana Telem. “Medicare Coding Changes and Reported Hernia Size.” JAMA (published online on Jan. 16, 2025).

The academic article showing that group incentives don’t seem to matter to surgeons is:

Srivastava, Arnav, Samuel R. Kaufman, Addison Shay, Mary Oerline, Xiu Liu, Monica Van Til, Susan Linsell, Corinne Labardee, Christopher Dall, Kassem S. Faraj, Avinash Maganty, Tudor Borza, Kevin Ginsburg, Brent K. Hollenbeck, and Vahakn B. Shahinian. “Physician Payment Incentives and Active Surveillance in Low-Risk Prostate Cancer.” JAMA Network Open 8, no. 1 (Jan. 8, 2025): e2453658-e58.

At Age 84 Scolnick Has the Passion to Persevere at Curing His Son’s Illness

Many of those with the passion to persevere in overcoming the necessary and unnecessary (regulatory) obstacles to medical innovation, do so because they have a sense of urgency due to skin in the game–they or a relative is directly affected by the disease they are passionate to cure. Dr. Edward Scolnick whose story I quote below, is a great example. In the story, we find another example, Ted Stanley, who donated $100 million to Scolnick because Stanley’s son is also suffering mental illness. And perhaps an indirect example? Rienhoff does not directly have skin in the game, but he is playing a key role because of Scolnick’s passion, and Scolnick’s passion is due to his skin in the game.

If we want more cures we will reduce the unnecessary (regulatory) obstacles so that those with less skin in the game (and so less passion to persevere) will also innovate.

[“Skin in the game” has been emphasized by Taleb in his book with that title.]

(p. A1) Dr. Edward Scolnick figures he needs five, maybe 10 more years to solve one of the brain’s greatest mysteries.

Scolnick, 84 years old, has spent most of the past two decades working to understand and find better ways to treat schizophrenia and bipolar disorder, mental illnesses suffered by tens of millions of people, including his son.

“I know I can crack it,” said Scolnick, a noted drug developer who spent his career plumbing the building blocks of DNA for new treatments.

Long before his latest quest, Scolnick spent 22 years at Merck, mostly as head of the drug giant’s laboratory research. He led development of more than two dozen medicines, including the first approved statin to lower cholesterol, an osteoporosis treatment and an anti-HIV therapy.

. . .

(p. A9) In 2021, Scolnick learned that a group of scientists analyzing DNA from thousands of people with schizophrenia had found mutations in 10 genes that substantially increased the risk of developing the illness. They estimated that a mutation on a single gene, called Setd1a, raised the risk 20-fold.

“It got my blood boiling,” Scolnick said. He began pursuing an emerging class of treatments called LSD1 inhibitors, hoping to develop a new drug. Scolnick enlisted Dr. Hugh Young Rienhoff Jr., who recently developed an LSD1 inhibitor to treat blood disorders.

. . .

Rienhoff anticipates testing a new drug for safety as early as next year, first in animals. He said he saw Scolnick’s passion about fielding a breakthrough treatment but didn’t fully understand why until Scolnick shared about his son’s lifelong struggles with mental illness.

Jason Scolnick, 54, said his doctor has been regularly fine-tuning his medications for bipolar disorder over the years to minimize their debilitating side effects. Using the drugs currently prescribed for schizophrenia or bipolar disorder is like undergoing chemotherapy, he said. “There’s no guarantee it will work and it makes you feel terrible, but the cancer will feel worse or kill you.”

There remains a long road ahead for any new medicine. It takes more than a decade, on average, to get a drug from the research lab through government approvals to patients.

. . .

After leaving Merck, Scolnick was hired in 2004 by the Broad Institute of MIT and Harvard to lead research on psychiatric disorders. He fostered ties with Ted Stanley, a memorabilia entrepreneur whose son also suffered with mental illness. In 2007, Stanley gave $100 million to launch the Stanley Center for Psychiatric Research at the Broad, headed by Scolnick for five years.

. . .

Scolnick and Rienhoff had sat together at a Blackstone dinner years earlier. During the meal, Scolnick shared stories with his table companions about Merck’s development of Crixivan, the anti-HIV drug. “I was hearing a piece of history,” Rienhoff said, “not just HIV history.”

Scolnick became emotional describing how the drug developers, facing various obstacles, wrestled with whether or not to keep going. He pushed for the study to continue, given the urgency. At the time, AIDS was killing tens of thousands of people a year in the U.S.

“I said to Ed, ‘You are thinking like a doctor not a scientist,’” Rienhoff said. “That was the beginning of our relationship.”

. . .

Rienhoff has a team of chemists making and testing compounds at labs in the U.S. and abroad.

“I am optimistic something will come of this,” Rienhoff said. “I can do it, but I wouldn’t have done it if not for Ed. I am, really, doing this in a way for Ed.”

. . .

Biotech company Oryzon Genomics in Spain is developing LSD1 inhibitors for cancer and other conditions. Columbia University researchers tried Oryzon’s drug in mice and found it reversed cognitive impairments caused by the Setd1a genetic mutation connected to schizophrenia. Oryzon is running a small trial in Spain of the LSD1 inhibitor in patients with schizophrenia.

Dr. Joseph Gogos, who led the Columbia research, said it was possible such treatments would be approved for people.

Scolnick is more certain—of both a revolutionary new treatment and his living to witness it.

“Before I die, we will see new medicines, new diagnostics, better outcomes for patients burdened by schizophrenia or bipolar illness,” he said. “I will not be happy to die. But I will die happy that my life helped.”

For the full story see:

Amy Dockser Marcus. “Aging Scientist Races Against Time.” The Wall Street Journal (Friday, Nov. 29, 2024): A1 & A9.

(Note: ellipses added.)

(Note: the online version of the story has the date November 26, 2024, and has the title “A Scientist’s Final Quest Is to Find New Schizophrenia Drugs. Will He Live to See Them?”)

The Free Market Gets a Bum Rap When Blamed for High and Chaotic Drug Prices

The Law of One Price in economics says that in the absence of transaction costs, similar goods will have the same price. If the price of a Tesla truck is $100,000 in Omaha and $200,000 in Des Moines, some enterprising arbitrager will buy a few in Omaha for $100,000, and sell them for slightly less than the going price in Des Moines. As the arbitrager arbitrages, the price of the truck in Omaha will converge with that in Des Moines, a close-enough confirmation of the Law of One Price. If this does NOT happen then either transaction costs are very high or we are not dealing with a free market. As the article quoted below shows, prices of medical drugs vary widely and persistently. Medical drugs are NOT sold in a free market. Arbitrage is NOT allowed. Who can sell to whom is highly regulated. To blame the free market for high and chaotic drug prices is an outrageous bum rap.

(p. A1) The cost of prescription drugs in the U.S. isn’t like the tabs for other products. The price for a single medicine can range by thousands of dollars depending on the drug plan.

It is a symptom of America’s complicated—and costly—system for paying for medicines.

Medicare is paying wildly different prices for the same drug, even for people insured under the same plan.

. . .

Take commonly used generic versions of prostate-cancer treatment Zytiga. They have more than 2,200 prices in Medicare drug plans. The generics ring in at roughly $815 a month in northern Michigan, about half of what they cost in suburban Detroit, while jumping to $3,356 in a county along Lake Michigan, according to a recent analysis of Medicare data.

The same is true with other popular medicines such as psoriasis treatment Otezla, blood thinner Xarelto and generic versions of the cancer drug Tykerb, known as lapatinib, which has 460 prices, according to the analysis by 46brooklyn Research, a nonprofit drug-pricing analytics group.

. . .

(p. A2) The reason for the huge price differences: America’s complicated drug-reimbursement system, which uses middlemen to negotiate prices.

. . .

Not only is it confusing and costly for seniors, the wide range of drug prices costs Medicare. The program, which farms out drug-price negotiations to the firms, pays tens of millions of dollars extra for prescriptions.

“It’s a broken system. It’s really confusing for seniors. It’s really confusing for providers. It’s costing the government way too much,” said Dared Price, who owns eight pharmacies in the Wichita, Kan., area, and complains the stores are underpaid.

The middlemen [are] known as pharmacy benefit managers or PBMs, . . .

. . .

“The inconsistent and disconnected way that PBMs arrive at drug prices makes Medicare look less like a trustworthy marketplace intended to yield low, sober prices and more like a casino,” said 46brooklyn Chief Executive Antonio Ciaccia.

. . .

To find out the prices that the big three and other PBMs negotiated, 46brooklyn looked at what standalone Part D and Medicare Advantage plans say they will reimburse pharmacies on behalf of Medicare for branded and generic drugs during the second quarter. They reported the prices that Medicare would pay.

Some 61 drugs had monthly prices that diverged by at least $30,000, including a $223,037 range for a drug, called nitisinone and sold under the brand name Orfadin, treating a rare metabolic disorder. About 300 medicines had more than 1,000 monthly prices when the difference between the lowest price and the highest was more than $1,000.

It didn’t matter that the same PBM was negotiating the prices. Prices varied widely among health plans, even if a plan used the same PBM.

The 30 mg dose of Otezla had among the most different prices among branded medicines. It had 633 different prices across health plans that used Express Scripts, while Optum Rx carried 569 different prices and Caremark had 431.

The largest PBMs notched some of the biggest number of different prices for lower-priced copies of Zytiga, which is sold as a generic under the drug’s chemical name abiraterone acetate.

Caremark has logged 643 different prices for Zytiga generics, while Express Scripts has 500 and Optum Rx carries 445. By comparison, Capital Rx, a PBM with fewer beneficiaries than the three largest firms, had two prices.

Capital Rx had few prices—either $106 or $117—because it pegged them to the benchmark that the U.S. government uses to calculate drug costs, called the National Average Drug Acquisition Cost, which is based on a survey of retail pharmacy prices, said Chief Executive Anthony Loiacono. Capital Rx’s prices were much less than the sums that many other health plans reported.

“We don’t make money on drug spend, and I do not set prices. I use what CMS gives us as the starting point,” Loiacono said.

For the full story see:

Jared S. Hopkins and Josh Ulick. “Medicare Payouts Vary Widely for Same Drug.” The Wall Street Journal (Wednesday, Nov. 27, 2024): A1-A2.

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

(Note: the online version of the story has the date November 26, 2024, and has the title “Same Drug, 2,200 Different Prices.” Where there is a slight difference in wording between the print and online versions, the passages I quote above follow the online version.)

Patients Are Too Patient About the Time They Waste in Worthless Healthcare

Healthcare appointments are often too numerous, too time-consuming, too stressful, and too harmful. Journalist Paula Span, often citing the words and research of MD Ishani Ganguli, presents this as an outrageous revelation. Dr. Ganguli tells us “there are opportunity costs” and “you don’t have infinite time, energy and attention” (Ganguli as quoted in Span 2024, p. D3). Outrageous it is, but to few of us is it a revelation. Patients know because they experience. If they are smart (I am often stupid) they will stifle their complaints so they do not annoy their care-givers. But care-givers know also. Those implementing the time-wasting or onerous practices are not evil. But they often do not have the incentive, or sometimes even the power, to change.

Every time I go into a doctor’s office, I am weighed. I always ask, “Do you want me to take my shoes off?” The nurse or medical assistant always shrugs and says they do not care. If my weight mattered, shouldn’t it be taken consistently, either always with shoes on or shoes off? I have had my weight taken countless times but I cannot remember a single time when the doctor mentioned the weight measure from earlier in the appointment. Prescription lists are endlessly requested, even by those who do the prescribing. Many lab tests are done out of the inertia of routine. In many hospitals sleeping patients are interrupted by a “care-giver” who comes in and performs a routine task, like asking them how much pain they are feeling. The “care-giver” records the answer and departs, taking no other action, but in the meantime diminishing the healing sleep of the patient. Tasks of this sort must be damaging to the morale of the care-giver. They signed up to do good, not to do harm. But they must do harm to follow the mandated protocol, or they risk being punished.

Why do these practices continue? Because they have been done in the past. No one will be rewarded for dropping them, and the care-giver who fails to do them is at risk of being criticized or punished. In a non-entrepreneurial, litigious, and highly regulated system, much that is done is not done for the benefit of the patient. It is done for CYA (“Cover Your Ass”).

But hope abides. We could deregulate healthcare. Then doctors could tell their nurses to only take the patient’s weight when it is actually needed. Hospital entrepreneurs could tell staff to only ask patients of their pain when they are awake and complaining of pain. Options in healthcare would be more diverse. But some of the options would actually make sense. Care-givers providing options that make sense would expand their own practice and be imitated by others. We would have better care and less wasted time.

The commentary by Paula Span, mentioned above, is:

Paula Span. “Too Much Time Spent on Doctors.” The New York Times (Tuesday, November 26, 2024): D3.

(Note: the online version of Span’s commentary has the date Nov. 23, 2024, and has the title “So Many Days Lost at the Doctor’s Office.”)

An academic article co-authored by Ganguli presents empirical evidence on how much time patients spend in healthcare activities:

Ganguli, Ishani, Emma D. Chant, E. John Orav, Ateev Mehrotra, and Christine S. Ritchie. “Health Care Contact Days among Older Adults in Traditional Medicare: A Cross-Sectional Study.” Annals of Internal Medicine 177, no. 2 (Feb. 2024): 125-33.

In an academic op-ed piece, Ganguli justly laments how the healthcare system often wastes patients’ time, sometimes even resulting in worse health. She uses the example of the severe cardiac side-effects from the eight weeks of Monday through Friday radiation that her 81-year-old father was given for his recently discovered prostate cancer:

Ganguli, Ishani. “How Does Health Care Burden Patients? Let Me Count the Days.” New England Journal of Medicine 391, no. 10 (Sept. 7, 2024): 880-83.

600,000 Americans Projected to Die of Cancer in 2025

Progress has been made against some specific cancers for some specific people. But overall there’s still a lot of cancer to be cured.

(p. A1) More Americans are surviving cancer, but the disease is striking young and middle-aged adults and women more frequently, the American Cancer Society reported on Thursday [Jan. 16, 2025].

. . .

Cancer is the second leading cause of death in the United States, but the leading cause among Americans under 85. The new report projects that some 2,041,910 new cases will occur this year and that 618,120 Americans will die of the disease.

Six of the 10 most common cancers are on the rise, including cancers of the breast and the uterus. Also increasing are colorectal cancers among people under 65, as well as prostate cancer, melanoma and pancreatic cancer.

For the full story see:

Roni Caryn Rabin. “Cancer Striking Younger Women.” The New York Times (Friday, January 19, 2025): A1 & A18.

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

(Note: the online version of the story was updated Jan. 17, 2025, and has the title “Cancer’s New Face: Younger and Female.”)

The academic article that is the basis for the summary statistics quoted above is:

Siegel, Rebecca L., Tyler B. Kratzer, Angela N. Giaquinto, Hyuna Sung, and Ahmedin Jemal. “Cancer Statistics, 2025.” CA: A Cancer Journal for Clinicians 75, no. 1 (Jan./Feb. 2025): 10-45.

Some of the key statistics from the academic article appear in:

American Cancer Society. “Cancer Facts & Figures 2025.” Atlanta: American Cancer Society, 2025.

Keep Raging at “the Dying of the Light”

I still remember as an undergraduate at Wabash College reading in our intro psychology textbook of an experiment in which a dog was put in a box. Every time the dog tried to leap out of the box, he received an electric shock. Eventually the electric current was turned off. But the dog never again tried to leap. Are we like the dog, too discouraged by past constraints, so that we are resigned to accept the Biblical limit of “three score and 10” (Psalm 90:10)?

But there is a paradox. Kloc cites an article claiming a very high market value for expanded lifespans. But then where are the voters urgently demanding that medical entrepreneurs be unbound? Where are the citizens demanding that regulators stop mandating Phase 3 clinical trials? Citizens with a sense of urgency can make a difference–see the Act-Up movement in the early years of AIDs. When will they?

(p. 1) The longevity industry is coming off perhaps its best run on record. The expected span of an American life has increased by about three decades since 1900 — to around 78 as of 2023. But for many people, even 78 years just won’t do.

The Methuselah Foundation, a biomedical charity, for example, wants to “make 90 the new 50,” and scientists at one biotechnology firm have argued that, unencumbered by disease, the body could potentially make it all the way to age 150. Even more optimistic estimates put the number closer to 1,000.

Whatever the maximum human life span may be, people appear increasingly determined to find it — in particular men, who are more inclined to favor radically extending life, maybe even indefinitely. Last year, nearly 6,000 studies of longevity made their way onto PubMed, a database of biomedical and life sciences papers; that’s almost five times as many as two decades ago.

Along with the creation of dozens of popular podcasts and a sizable supplement industry, that zeal has led to efforts to preserve organs, search out life-extending diets and even try to reverse aging itself.

. . .

(p. 24) Researchers at Harvard and Oxford recently tried to gauge that interest in the marketplace today. They estimated that the total value of any scientific breakthrough that added another decade to global life expectancy would be worth $367 trillion.

For the full story see:

Joe Kloc. “Gilgamesh, Ponce and the Quest to Live Forever.” The New York Times, First Section (Sunday, January 19, 2025): 1 & 24.

(Note: ellipsis added.)

(Note: the online version of the story has the date Jan. 18, 2025, and has the title “The Centuries-Old, Incredibly Male Quest to Live Forever.”)

When Kloc mentions estimates of possible human lifespan “closer to 1,000” he links to a Scientific American interview with João Pedro de Magalhães, professor of biogerontology at England’s University of Birmingham. João Pedro de Magalhães believes that in principle humans could live to 1,000:

Gifford, Bill. “How Old Can Humans Get?” Scientific American (July 31, 2023). Available from https://www.scientificamerican.com/article/how-old-can-humans-get/.

When Kloc says that some “even try to reverse aging itself” he links to:

Poganik, Jesse R., Bohan Zhang, Gurpreet S. Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T. Lu, Amin Haghani, Tong Gong, Anna M. Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B. Clish, Steve Horvath, James P. White, and Vadim N. Gladyshev. “Biological Age Is Increased by Stress and Restored Upon Recovery.” Cell Metabolism 35, no. 5 (2023): 807-20.

Kloc also links to estimates of the economic value of extending lifespans by one year, and by a decade, as given in:

Scott, Andrew J., Martin Ellison, and David A. Sinclair. “The Economic Value of Targeting Aging.” Nature Aging 1, no. 7 (July 2021): 616-23.

“Rage, rage against the dying of the light” is a line from Dylan Thomas’s poem “Do Not Go Gentle Into That Good Night.”

For Quicker Cures, Do Not Cancel Those Who See What We Do Not See

Dogs smell odors that we do not smell. They say Eskimos can distinguish 40 or more kinds of snow. Physical differences in biology and differences in past experiences allow some people to perceive what other people miss. We should encourage, not cancel, those who see differently. They can communicate and act on what they see, giving us more cures more quickly.

In the passages quoted below, a case is made that Pasteur’s artistic experiences allowed him to see a structural difference (chirality) in crystals; a difference that turns out to matter for medical drug molecules.

(p. D5) In a paper published last month in Nature Chemistry, Dr. Gal explains how a young Pasteur fought against the odds to articulate the existence of chirality, or the way that some molecules exist in mirror-image forms capable of producing very different effects. Today we see chirality’s effects in light, in chemistry and in the body — even in the drugs we take.

And we might not know a thing about them if it weren’t for the little-known artistic experience of Louis Pasteur, says Dr. Gal.

. . .

As a teenager, Pasteur made portraits of his friends, family and dignitaries. But after his father urged him to pursue a more serious profession — one that would feed him — he became a scientist. At the age of 24 he discovered chirality.

To understand chirality, consider two objects held up before a mirror: a white cue ball from a pool table and your hand. The reflection of the ball is exactly like the original. If you could reach into that mirror, pull out the reflection and cram it inside the original, they’d match up point for point. But if you tried the same thing with your hand, no matter how much you tried, the mirror image would never fit into the original.

At the molecular level some objects are like cue balls, and they are always superimposable. But other things are like hands, and they can never be combined.

. . .

During winemaking, a chemical called tartaric acid builds up on vat walls. In the 18th and 19th centuries, makers of medicine and dyes used this acid.

In 1819, factory workers boiled wine too long and accidentally produced paratartaric acid, which had unique properties that intrigued scientists like Pasteur.

. . .

When studying the paratartaric acid, Pasteur found that it produced two kinds of crystals — one like those found in tartaric acid and another that was the mirror opposite. The crystals were handed, or what the Greeks call chiral (kheir) for hand.

. . .

“Several famous or much more accomplished scientists, some well along their illustrious careers, studied the same molecules, the same substances,” said Dr. Gal. “Realistically you would think they’d have beaten him to the punch, and yet they missed it.”

So why did this young, inexperienced chemist get it right?

Dr. Gal thinks the answer might lie in the artistic passions of Pasteur’s youth. Even as a scientist, Pasteur remained closely connected to art. He taught classes on how chemistry could be used in fine art and attended salons. He even carried around a notebook, jotting down 1-4 ratings of artwork he visited.

And then Dr. Gal stumbled upon a letter Pasteur had written to his parents about a lithographic portrait he had made of a friend.

Lithography back then involved etching a drawing onto a limestone slab with wax or oil and acid, and pressing a white piece of paper on top of it. The resulting picture was transposed, like a mirror image of the drawing left on the slab.

In his letter, Pasteur wrote:

“I think I have not previously produced anything as well drawn and having as good a resemblance. All who have seen it find it striking. But I greatly fear one thing, that is, that on the paper the portrait will not be as good as on the stone; this is what always happens.”

Eureka. “Isn’t this the explanation of how he saw the handedness on the crystals — because he was sensitized to that as an artist?” Dr. Gal proposed.

. . .

We now know that many drugs contain molecules that exist in two chiral forms, and that the two forms can react differently in the body. The most tragic example occurred in the 1950s and ’60s, when doctors prescribed Thalidomide, a drug for morning sickness and other ailments, to pregnant women. The drug also contained a chiral molecule that caused disastrous side effects in many babies.

For the full story see:

Joanna Klein. “How Pasteur’s Artistic Insight Changed Chemistry.” The New York Times (Tuesday, June 20, 2017 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the story has the date June 14, 2017 [sic], and has the same title as the print version.)

The academic article in Nature Chemistry authored by Gal and mentioned above is:

Gal, Joseph. “Pasteur and the Art of Chirality.” Nature Chemistry 9, no. 7 (2017): 604-05.

Ozempic 25 Years Sooner Would Have Saved and Improved Many Lives

Apparently Ozempic had been discovered in the late 1980s and could have been on the market roughly 25 years ago. Pfizer decided that the likely potential revenues were not sufficient to justify the huge costs. But what if the costs had not been so huge? For instance what if we adopted the proposal suggested by Milton Friedman, and advocated by me, to stop mandating hyper-expensive Phase 3 clinical trials to prove efficacy? (The mandates to prove safety through Phase 1 and Phase 2 trials would be retained.) With lower costs, Pfizer might have moved forward. Or if Pfizer had not, some other firm probably would have entered the breach sooner. If Ozempic had been available sooner, by now it would be much cheaper. Many lives would have been saved that have been lost. Other lives would have been healthier and happier.

(p. A26) They called 2023 the year of Ozempic, but it now seems GLP-1 drugs might define an entire decade — or an even longer era. The game-changing drugs, which mimic the hormone GLP-1, offer large benefits for not just diabetes management and especially weight loss but also, apparently, heart and kidney and liver disease, Alzheimer’s and dementia, Parkinson’s and addiction of all kinds. And perhaps because of widespread use of the drugs, the obesity epidemic in America may finally and mercifully be reversing.

But of all the things we learned this year about GLP-1s, the most astonishing could be that the revolution might have started decades earlier. Researchers identified the key breakthrough for GLP-1 drugs nearly 40 years ago, it turns out, long before most Americans had even heard the phrase “obesity epidemic.”

This summer, a former dean of Harvard Medical School, Jeffrey Flier, published a long personal reflection that doubled as an alternate history of what may well be the most spectacular and impactful medical breakthrough of the century so far. In 1987, Flier co-founded a biotech start-up that pursued GLP-1 as a potential treatment for diabetes, not long after it had first been identified by researchers who’d also found that the hormone enhanced insulin secretion in the presence of glucose.

The startup obtained worldwide rights to develop GLP-1 as a metabolic therapy from a group of those researchers, based at Massachusetts General Hospital. They even generated clinical results that suggested it might have promise as a weight-loss drug as well — only to have Pfizer, which had agreed to fund the research, withdraw its support, without providing the researchers with an especially satisfying explanation. Instead, Pfizer told Flier and his partners that the company didn’t believe there would be a market for another injectable diabetes treatment after insulin. Well, Flier tells me, “they were wrong.”

. . .

. . . Flier’s memoir is not just a lament for what might have been. In the aftermath of the pandemic emergency, as citizens and officials alike have embraced a more libertarian attitude toward public health, there’s been a similar drift in the public conversation about drug discovery and development. Operation Warp Speed is often held up as a new model — calls for an Operation Warp Speed 2.0 have been followed by those for an Operation Warp Speed for everything — . . .

Many of the same reformers will complain about all the red tape at the F.D.A. and C.D.C., tallying up huge mortality costs imposed by slow-moving government, arguing for human challenge trials in which individuals volunteer to take untested drugs and be deliberately infected and even talking about the invisible graveyard of unnecessary regulation and delay.

This is all fine and good — there are surely lots of things those agencies can speed up. And in recent years, reformers of various stripes have lobbied some worthy additional proposals into the biomedical zeitgeist — for a system based not on patents but on huge and direct cash prizes for medical breakthroughs, for instance, or one helped along by advance market commitments or benevolent patent extensions. Just last week the researchers Willy Chertman and Ruxandra Tesloianu published “The Case for Clinical Trial Abundance,” an invigorating manifesto for drug development reform.

. . . in focusing on government bureaucracy as the major biomedical bottleneck, we are seeing just one piece of the picture and overlooking what is perhaps the central challenge of research and development — that it is, at present, so complicated that difficulties or bad decisions at any stage can stifle the whole decades-long process, distorting the actual medical and public-health functions of drug development in countless ways.

For the full commentary see:

David Wallace-Wells. “We Could Have Had Ozempic Years Ago.” The New York Times, SundayOpinion Section (Sunday, Jan. 5, 2025): 11.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Dec. 25, 2024, and has the title “Pfizer Stopped Us From Getting Ozempic Decades Ago.”)

Dr. Flier’s published “memoir” mentioned above is:

Flier, Jeffrey S. “Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.” Perspectives in Biology and Medicine 67, no. 3 (Summer 2024): 325-36.

“The Clinical Trial Manifesto” mentioned above is the introductory essay in the compilation referenced below. Another essay that looks promising in the compilation is “Unblocking Human Challenge Trials for Faster Progress.”

Chertman, Willy, and Ruxandra Tesloianu, eds. The Case for Clinical Trial Abundance: A Series of Short Papers Outlining Reform Possibilities for Our Nation’s Clinical Trials. Washington, DC: The Institute for Progress (IFP), 2024.

In 2023, Costs of Medical Care Rose 40% Faster Than Overall Inflation

If rising healthcare costs were clearly due to improving health outcomes, few would be angry. The anger arises from rising fraud, inefficiency, and inertia. Many healthcare workers are paper pushers and the paper pushed is often inaccurate and opaque. Other healthcare workers enforce protocols that slow innovation. And of course mandated regulations, most notably Phase 3 clinical trials, enormously increase costs.

(p. A3) The killing of a health insurance executive in New York City prompted a furious outpouring of anger over the industry and healthcare prices. So just how much have healthcare costs and spending been going up?

The short answer: a lot. National healthcare spending increased 7.5% year over year in 2023 to $4.867 trillion, or $14,570 per person, according to data released Wednesday by the Centers for Medicare and Medicaid Services.

. . .

The 7.5% rise represented a much faster pace of growth than the 4.6% increase in 2022.

. . .

Over the past couple of decades, the price index for what the Labor Department classifies as medical care—which includes visits to doctors, hospital stays, prescription drugs and medical equipment—has risen roughly 40% faster than the overall pace of inflation. Healthcare tends to rise more quickly than overall inflation because of high labor costs in the sector, as well as advancements leading to new and more expensive drugs and treatments. Demand for healthcare is also increasing as the population ages.

. . .

Hospitals are . . . adding billions of dollars in “facility fees” to medical bills for routine care at outpatient centers, according to reporting by The Wall Street Journal. That means patients are often paying hundreds of additional dollars for standard care like colonoscopies, mammograms and heart screenings.

. . .

Employers are shouldering a lot of those costs. For example, the average worker spent $6,296 in premiums for family coverage in 2024, according to KFF [a healthcare nonprofit]. Employers spent $19,276.

But when a company is paying more for insurance premiums for its workers, that leaves it with less money for giving out raises or reinvesting and expansion.

“It’s ultimately all of us who pay for [healthcare] either in the form of lower wages for people who have employer insurance or in the form of higher taxes to cover Medicare and Medicaid,” said Katherine Baicker, professor of health economics at the University of Chicago.

For the full story see:

Harriet Torry. “Nation’s Healthcare Tab Is Surging Amid Rising Wages, Hospital Fees.” The Wall Street Journal (Friday, Dec. 20, 2024): A3.

(Note: ellipses added. The first bracketed words were added by me; the second bracketed word was in the original.)

(Note: the online version of the story was updated December 18, 2024, and has the title “Why Are Americans Paying So Much More for Healthcare Than They Used To?” Where there is a slight difference in wording between the print and online versions, the passages I quote above follow the online version.)

The source for some of the data discussed in The New York Times article appears to have been:

“National Health Expenditures 2023 Highlights.” Centers for Medicare & Medicaid Services (CMS), Last modified on Dec. 18, 2024.

Higher Fluoride in Water Correlated with Lower I.Q. in Children

When I was young, in the 1960s, I remember my family opposing the government fluoridation of the South Bend, Indiana water supply, even though our dentist, Dr. Stan Severyn, who we liked and respected, was in favor of fluoridating South Bend water. We thought that when consumed in water, fluoride was a cumulative poison, and we thought the dental benefits of fluoride could be obtained through applying fluoride directly to the teeth (as Dr. Severyn did to my teeth) or through the careful use of fluoridated toothpaste.

My memory is that the South Bend city council overwhelmingly approved adding fluoride to the city waster. My family was in a small minority and our views were widely dismissed. But small minorities are not always wrong. See The New York Times article quoted below. Or see the history of medicine more broadly, for instance when Ignaz Semmelweis was in a small minority suggesting that physicians returning from dissections in the morgue should wash their hands before delivering babies.

When our daughter Jenny was very young, I read that very young children often accidentally swallow toothpaste when they start brushing their own teeth. Then, as now, almost all toothpaste contained fluoride. So when Jenny reached the age of brushing I searched the shelves of several Omaha stores seeking non-fluoridated toothpaste. I finally found a couple of tubes, imported from Sweden I think, in a now defunct store called The Drug Emporium. Jenny used that toothpaste until she was old enough to reliably spit out the toothpaste after brushing.

[In the passages quoted below, “JAMA” stands for The Journal of the American Medical Association which, along with The New England Journal of Medicine and The Lancet, is widely considered to be one of the handful of top medical journals in the world. JAMA Pediatrics is one of several JAMA-associated field journals.]

(p. 19) Water fluoridation is widely seen as one of the great public health achievements of the 20th century, credited with substantially reducing tooth decay. But there has been growing controversy among scientists about whether fluoride may be linked to lower I.Q. scores in children.

A comprehensive federal analysis of scores of previous studies, published this week in JAMA Pediatrics, has added to those concerns. It found a significant inverse relationship between exposure levels and cognitive function in children.

Higher fluoride exposures were linked to lower I.Q. scores, concluded researchers working for the National Institute of Environmental Health Sciences.

. . .

The subject is so divisive that JAMA Pediatrics commissioned two editorials with opposing viewpoints to publish alongside the report.

In one, Dr. Steven M. Levy, a public health dentist at the University of Iowa, said that many of the studies included in the analysis were of very low quality.

. . .

In a second editorial published alongside the new study, a public health expert, Dr. Bruce P. Lanphear, noted that as far back as 1944, the editor of The Journal of the American Dental Association expressed concern about adding fluoride, which he termed “a highly toxic substance,” to drinking water. He wrote that “the potentialities for harm far outweigh those for good.”

Some studies have suggested that dental health has improved not because fluoride was added to water, but because of fluoridated toothpastes and better dental hygiene practices.

. . .

Some 74 studies from 10 countries, including China, Mexico, Canada, India and Denmark, were examined. Dr. Lanphear noted that the consistent links between fluoride and I.Q. were found in very different populations.

He urged the U.S. Public Health Service to set up a committee, perhaps one that does not include researchers who have studied the subject in the past and can take a fresh look at the topic, to examine two questions seriously: whether fluoride is neurotoxic, and whether it is as beneficial for oral health as it is believed to be.

“If that doesn’t happen urgently, my concern is there will be growing distrust of public health agencies amid the public, and they will have deserved it,” he said.

For the full story, see:

Roni Caryn Rabin. “High Fluoride Exposure Is Linked to Lower I.Q. In Children, Study Finds.” The New York Times, First Section (Sunday, January 12, 2025): 19.

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

(Note: the online version of the story has the date January 8, 2025, and has the title “Study Links High Fluoride Exposure to Lower I.Q. in Children.”)

The JAMA Pediatrics academic article mentioned above is:

Taylor, Kyla W., Sorina E. Eftim, Christopher A. Sibrizzi, Robyn B. Blain, Kristen Magnuson, Pamela A. Hartman, Andrew A. Rooney, and John R. Bucher. “Fluoride Exposure and Children’s IQ Scores: A Systematic Review and Meta-Analysis.” JAMA Pediatrics (published online on Jan. 6, 2025).