Science – artdiamondblog.com

Allow Those with Skin in the Game to Help Find Quicker Cures

The New York Times devoted more than two and half full pages to the article that I quote from below. Very very few articles receive that much space. The story is meant to inspire and it does. Linde has a terrible genetic disease, as did her mother and grandmother, as do her two sisters, and as might her two daughters. She is uncredentialled, but determined. She reads scientific articles, gives talks at scientific meetings, creates a foundation to raise funds, and with her sisters gave samples from her skin to create cell lines that can be used for research to find a cure. Linde, both literally and figuratively, has skin in the game.

In the article, victims of the disease wish that there were more clinical trials to test more possible cures. If the price of clinical trials were lower, more of them would be supplied. One way to reduce the price would be for the F.D.A. to only mandate testing for safety, not to mandate testing for efficacy. After all, it was concerns over the safety, not the efficacy, of thalidomide, that first accelerated the F.D.A.’s clinical trial mandates. Testing only for safety (Phase 1 and Phase 2 clinical trials), would hugely reduce the price, resulting ultimately in more and quicker cures.

(p. A1) Linde Jacobs paced back and forth across her bedroom, eyeing the open laptop on the dresser and willing the doctor to appear. Her husband was dropping off their older daughter at school. Their younger daughter was downstairs, occupied by a screen. Linde wanted to be alone when she learned whether she carried the family curse.

Linde’s mother, Allison, had died just four weeks before, after a mutant gene gradually laid waste to her brain. In her 50s, Allison transformed from a joyful family ringleader into an impulsive, deceptive pariah. She drove like a maniac on cul-de-sacs. She pinched strangers, shoplifted craft supplies and stole money from her daughter.

Now, on this morning in September 2021, Linde would find out if she had inherited the same vile genetic mutation.

. . .

The doctor finally popped up on the computer. Wasting no time on pleasantries, she shared her screen and zoomed in on one line of laboratory paperwork: POSITIVE.

. . .

Soon, Linde’s husband, Taylor, pulled into the garage and opened the car door. He could hear her sobbing.

. . .

Linde looked at Taylor. “I don’t want you to feel stuck with me,” she said.

(p. A12) Leaving had never crossed his mind. Allison’s miserable experience, he told Linde, did not have to be hers. “You have all this time,” he said. “Do something about it.”

Even as they spoke, scientists were working on projects that might one day help her. Some had discovered how to cure grave conditions with gene editing. Others were tinkering with patients’ skin cells to test experimental drugs. And pharmaceutical companies were developing new Alzheimer’s therapies, one of which happened to target the rare defect in Linde’s brain.

Linde didn’t know any of that yet. But she decided to take Taylor’s advice. She would use the time she had, somehow, to find influential scientists and make them care about what was happening to her — and what might happen to her girls.

Linde and Taylor scoured the internet for any scrap of hope about treating frontotemporal dementia, or FTD. There was little to read.

Taylor remembered a Netflix documentary about a new way to edit genes. The method, called CRISPR, had cured some children with sickle cell disease. He searched “FTD treatment CRISPR” and found the website of Dr. Claire Clelland, a neurologist at the University of California, San Francisco. She had collected skin cells from patients with FTD, reprogrammed them into neurons and tried to edit the faulty genetic code within.

The website listed a phone number. Taylor called and left a message — a Hail Mary, he figured.

Within a day, Dr. Clelland responded by email. “Happy to help if I can,” she wrote.

. . .

(p. A13) “Could I ask a question?” one young scientist said. How much risk, she wondered, was Linde comfortable taking on an experimental treatment? Editing genes with CRISPR was new, after all, and could come with serious side effects.

“Sign me up, patient zero, sounds good,” Linde said.

“What choice do I have,” she added, “if I don’t want the same future for myself as my mom had, and her mom?”

When she wasn’t working or coaching her daughter’s soccer team, Linde threw herself into the scientific research on MAPT — a niche but growing subfield. The gene provides the instructions for cells to make tau, a protein in the brain.

One day she came across news of a project investigating how tau can go awry. She wrote to the scientist leading the work, Dr. Kenneth Kosik of the University of California, Santa Barbara, describing her family and asking to talk.

Dr. Kosik was sitting in his home office when her note landed in his inbox. “It was the second time in my life that I realized, I’ve got to get back to this person in, like, a nanosecond,” he recalled.

. . .

Dr. Kosik told Linde that an elite group of researchers, known as the Tau Consortium, would gather in Boston in a few months for its annual meeting. Dr. Clelland would be there, as would other “Michael Jordans” in the field. We should try to get you there, he said, so the scientists can be reminded of the human toll of tau-related diseases.

A few weeks later, Linde received an invitation to be the keynote speaker. Jenica and Ashlyn could come, too.

She texted her sisters, “Holy shit.”

One morning in Boston in June 2023, Linde and her sisters got all dolled up, only to arrive in a grand hotel ballroom filled with 100 scientists in oxfords and sneakers.

Dr. Kosik introduced Linde to the members of the Tau Consortium. Too nervous to look anyone in the eye, she stared at a screen showing her slides and read from her prepared remarks.

“You will notice the lack of credentials following my name,” she began. But she said her life had brought her other titles: Caregiver. Jail-Bailer. Carrier. She was the heartbeat, she said, of the cells they studied.

. . .

After the Boston talk, Linde received a flurry of invitations to tell her story. She was interviewed on YouTube by Emma Heming Willis, the wife of the actor Bruce Willis, the most famous person known to have frontotemporal dementia. She came face to face with monkeys that carried MAPT mutations in Madison, Wis. And though she detested the crowds and grime of big cities, she flew to places like Philadelphia and Washington, D.C., to at-(p. A14)tend scientific meetings.

Linde, who by then had moved to River Falls, Wis., always returned home exhausted. But the trips were also fortifying. Learning about the latest research quelled her anxiety — and her husband’s. . . .

During her travels, Linde met other families with MAPT mutations. They were all frustrated by the lack of clinical trials for their genetic glitch, especially because several promising treatments were in the pipeline for other dementia genes. Linde and the others started a global survey of people with MAPT mutations. If an opportunity came along for a clinical trial, they would make it as easy as possible for scientists to find volunteers.

. . .

A few months later, Linde and the group started a nonprofit, called Cure MAPT FTD. They have since found more than 500 people with confirmed or possible MAPT mutations in 10 countries, all of whom have expressed interest in participating in future clinical trials.

In March of this year, Linde got an astonishing offer from Dr. Clelland. Along with collaborators at Washington University and the Neural Stem Cell Institute in New York, she wanted to collect skin cells from Linde and her sisters and turn them into clusters that divide infinitely, known as cell “lines.”

“We propose to make new lines that can be shared with academics and also with industry so that people can do drug screening” and CRISPR projects, Dr. Clelland wrote.

. . .

Based on what happened to Allison and Bev, Linde figures she has at least 10 more years before she starts showing symptoms. But there’s no guarantee; some MAPT carriers begin to change in their 20s. Whenever Linde tells a joke a little too loudly, or has a dulled emotional response to a dramatic event, she worries: Is this tau?

That anxious metronome never shuts off. It compels her to fill any moment of downtime reading the latest study or sending another email. She has spent thousands of dollars and hundreds of unpaid hours on travel. But sometimes, like when she finds herself alone in a hotel room, FaceTiming her daughter about a rough day at school, she questions whether these scientific pursuits are really the best way to run out the clock.

. . .

Dr. Clelland said designing a CRISPR molecule that could precisely excise the MAPT mutation from a cell’s genome was not the hard part. The major unsolved challenge is delivering those molecular scissors into the brain. Still, she and her colleagues at U.C.S.F. have set an ambitious goal of getting MAPT therapy into clinical trials within four years.

For the full story see:

Virginia Hughes. “A Mother’s Race to Beat a Genetic Time Bomb.” The New York Times (Wednesday, December 25, 2024): A1 & A12-A14.

(Note: ellipses added.)

(Note: the online version of the story was updated Jan. 2, 2025, and has the title “Fighting to Avoid Her Mother’s Fate, for Her Daughters’ Sake.” I have omitted a few subhead titles that appear in both the online and print versions.)

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.

Reductio ad Absurdum: When a Functional MRI Showed Activity in a Dead Salmon’s Brain

I have long thought that most college students would benefit from a course in practical reasoning. One topic in such a course would be to define and illustrate the Reductio ad Absurdum argument. The argument starts with a proposition, and then infers an absurdity from the proposition, thereby refuting the original proposition. The review quoted below mentions such an argument that implicitly starts with the proposition that fMRI scans are reliable guides to human thought. The absurdity is that fMRI scans sometimes light up in the presence of a dead Atlantic salmon, which would seem to suggest that the salmon is thinking. The conclusion: be careful what you infer from fMRI scans.

My favorite reductio ad absurdum argument starts with the proposition that all actionable knowledge must derive from randomized double-blind clinical trials (RCTs). The argument then shows that no RCTs have been performed to show the efficacy of parachutes. The absurdity is that before anyone uses a parachute when exiting a flying airplane, he must first find an RCT to prove the efficacy of parachutes. The conclusion: when you volunteer for the first such RCT, hope that you are not assigned to the control group!

(p. A15) In 2009 a group of researchers placed a dead salmon in a functional magnetic resonance imaging (fMRI) scanner and showed the fish some photos of people in social situations. Their results, presented under the title “Neural Correlates of Interspecies Perspective Taking in the Post-Mortem Atlantic Salmon,” were surprising. The scans revealed a red spot of activity centered in the salmon’s brain.

The authors of the study weren’t trying to pull a fast one on the scientific community. Nor did they believe in zombie fish. They were showing that statistics, used incorrectly, can demonstrate almost anything. Specifically, a certain type of data analysis, often used on fMRI scans, can find signal where there should be only noise.

Russell Poldrack, a psychologist at Stanford University, mentions the stunt in “The New Mind Readers: What Neuroimaging Can and Cannot Reveal About Our Thoughts.” His book, ostensibly about fMRI and its use in studying how the brain functions (hence “functional”), serves as a lesson in how the science works—or should work. Through blunders and baloney, innovation and self-correction, the young field of cognitive neuroscience is quickly evolving.

For the full review see:

Matthew Hutson. “Bookshelf; Scanning For Thoughts.” The Wall Street Journal (Wednesday, November 28, 2018 [sic]): A15.

(Note: the online version of the review has the date November 27, 2018 [sic], and has the title “Bookshelf; ‘The New Mind Readers’ Review: Scanning for Thoughts.”)

The book under review is:

Poldrack, Russell. The New Mind Readers: What Neuroimaging Can and Cannot Reveal About Our Thoughts. Princeton, NJ: Princeton University Press, 2018.

The parachute reductio argument is in:

Smith, Gordon C. S., and Jill P. Pell. “Parachute Use to Prevent Death and Major Trauma Related to Gravitational Challenge: Systematic Review of Randomised Controlled Trials.” BMJ 327, no. 7429 (Dec. 18, 2003): 1459-61.

To Kill a Dam, Environmentalist “Scientists” Lied About the Existence of the So-Called “Snail Darter”

In the 1970s the building of a dam in Tennessee was delayed because environmentalists claimed that its construction would threaten the extinction of a small fish they called the “snail darter.” Now fish biologists have established that there is no snail darter. The fish previously identified as a “snail darter” has the DNA of a small fish called a “stargazing darter” which was not, and is not, endangered.

A co-author of a new study says that this was no innocent mistake.

Dr. Near, . . . a professor who leads a fish biology lab at Yale, and his colleagues report in the journal Current Biology that the snail darter, Percina tanasi, is neither a distinct species nor a subspecies. Rather, it is an eastern population of Percina uranidea, known also as the stargazing darter, which is not considered endangered.

Dr. Near contends that early researchers “squinted their eyes a bit” when describing the fish, because it represented a way to fight the Tennessee Valley Authority’s plan to build the Tellico Dam on the Little Tennessee River, about 20 miles southwest of Knoxville.

“I feel it was the first and probably the most famous example of what I would call the ‘conservation species concept,’ where people are going to decide a species should be distinct because it will have a downstream conservation implication,” Dr. Near said.

In other words environmentalist “scientists” deliberately lied in order to promote their political agenda of cutting energy production.

The New York Times article quoted above is:

Jason Nark. “How a Mistaken Identity Halted a Dam’s Construction.” The New York Times (Sat., Jan. 4, 2025): A13.

(Note: ellipsis added.)

(Note: the online version of The New York Times article was updated Jan. 4, 2025, and has the title “This Tiny Fish’s Mistaken Identity Halted a Dam’s Construction.”)

The academic paper co-authored by Near, that Nark summarizes in The New York Times article mentioned and cited above is:

Ghezelayagh, Ava, Jeffrey W. Simmons, Julia E. Wood, Tsunemi Yamashita, Matthew R. Thomas, Rebecca E. Blanton, Oliver D. Orr, Daniel J. MacGuigan, Daemin Kim, Edgar Benavides, Benjamin P. Keck, Richard C. Harrington, and Thomas J. Near. “Comparative Species Delimitation of a Biological Conservation Icon.” Current Biology. Published online on Jan. 3, 2025.

“Trusting the Experts Is Not a Feature of Science. It’s the Opposite of Science.”

Over my desk, in the biggest font my printer will print, I have the Latin motto “Nullius in Verba.” That is the motto of the Royal Society of London, the first association for the advancement of science. In English the motto says “on no one’s word” and is usually interpreted to mean that if we are doing science we rely on evidence, and not on the authority of experts. C.S. Peirce said truth is what results from infinite inquiry. Science is a process of asking questions, not a body of unquestionable truths. During the Covid pandemic we were told to stop asking questions and blindly accept the orders of “experts” who the government identified as scientists. Citizens who valued free speech and understood Nullius in Verba rebelled.

Vaccines and antibiotics are two of the greatest achievements in medicine. But both have side-effects and risks. By denying the real side-effects and risks of Covid vaccines, the “experts” destroyed their credibility with the thinking (i.e., the scientific) public. The public’s anger at being lied to was so great that some went so far as to reject all vaccines, even in the frequent situation where on balance the benefits of the vaccine outweigh the side-effects and risks. This was the unnecessary, outrageous, and sad result of government regulators who did not value freedom and did not understand the meaning of “science.”

(p. A1) The rise of Robert F. Kennedy Jr. from fringe figure to the prospective head of U.S. health policy was fueled by skepticism and distrust of the medical establishment—views that went viral in the Covid-19 pandemic.

. . .

Lingering resentment over pandemic restrictions helped Kennedy and his “Make America Healthy Again” campaign draw people from the left and the right, voters who worried about the contamination of food, water and medicine. Many of them shared doubts about vaccines and felt their concerns were ignored by experts or regarded as ignorant.

. . .

(p. A8) Much of Kennedy’s popularity reflects residual pandemic anger—over being told to stay at home or to wear masks; the extended closure of schools and businesses; and vaccine requirements to attend classes, board a plane or eat at a restaurant.

“We weren’t really considering the consequences in communities that were not New York City,” the places where the virus wasn’t hitting as hard, former National Institutes of Health Director Francis Collins said at an event last year.

Authorities focused on ways to stop the disease and failed to consider “this actually, totally disrupts peoples’ lives, ruins the economy and has many kids kept out of school,” Collins said. The U.S. overall took the right approach, he said, but overlooking long-term consequences was “really unfortunate. That’s another mistake we made.”

. . .

. . ., Jessica Malaty Rivera, an epidemiologist with hundreds of thousands of Instagram followers, shared information on the importance of vaccines and face masks. She dismissed unsupported claims as misinformation and described some of their purveyors as grifters.

Looking back, Rivera said her sometimes scolding messages weren’t helpful. “Everybody has been tempted by the slam dunk,” she said. “It’s not an effective way to communicate science. It’s just not.” She and others say they are dialing back the use of the word misinformation, saying it makes people feel they are being called liars or dumb.

During the pandemic, Palmira Gerlach had questions about the Covid-19 vaccines, but doctors “were very dismissive,” the 44-year-old recalled.

Gerlach, a stay-at-home mother outside Pittsburgh, said she falsely told her child’s pediatrician that she got the shot, seeking to avoid judgment. The doctor told her, “Good girl.” Gerlach turned to podcasts featuring Kennedy, drawn to his willingness to question pandemic measures.

. . .

“We were all told in Covid: ‘Trust the experts.’ But that’s not a thing,” Kennedy said in an episode of the “What is Money?” podcast in April [2024]. “Trusting the experts is not a feature of science. It’s the opposite of science. It’s not a feature of democracy.”

For the full story see:

Liz Essley Whyte. “How Science Lost America’s Trust.” The Wall Street Journal (Thursday, Nov. 21, 2024): A1 & A8.

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

(Note: the online version of the story has the date November 19, 2024, and has the title “How Science Lost America’s Trust and Surrendered Health Policy to Skeptics.” In passages where the online version is more detailed, I quote from the online version.)

Innovative Medical Project Entrepreneur Karikó Long Persevered to Develop mRNA Technology Behind Covid-19 Vaccines

The basic science and technology behind mRNA did not come easy and did not come quick. If the skeptics of Covid-19 vaccines knew this they might be less skeptical because one of the reasons they sometimes give for their skepticism is the speed with which the vaccines were developed. (Other reasons for skepticism I think are more defensible, such as the worry that the authorities downplayed the real side-effects that some vaccine recipients suffered from the vaccines. But on balance I still think the vaccines were a great achievement.) One of the heroes of the long slog is Katalin Karikó. Part of her story is sketched in the passages quoted below. She is a good example of an innovative medical project entrepreneur. When she was named a winner of the Nobel Prize she identified part of what it takes to succeed: “we persevere, we are resilient” (Karikó as quoted in Mosbergen, Loftus, and Zuckerman 2023, p. A2).

(p. A2) The University of Pennsylvania is basking in the glow of two researchers who this week were awarded the Nobel Prize in medicine for their pioneering work on messenger RNA.

Until recently, the school and its faculty largely disdained one of those scientists.

Penn demoted Katalin Karikó, shunting her to a lab on the outskirts of campus while cutting her pay. Karikó’s colleagues denigrated her mRNA research and some wouldn’t work with her, according to her and people at the school. Eventually, Karikó persuaded another Penn researcher, Drew Weissman, to work with her on modifying mRNA for vaccines and drugs, though most others at the school remained skeptical, pushing other approaches.

. . .

. . . on Monday [Oct. 2, 2023], when Karikó and Weissman were awarded the Nobel, on top of prestigious science prizes in recent years, the school expressed a different perspective on their work.

The reversal offers a glimpse of the clubby, hothouse world of academia and science, where winning financial funding is a constant burden, securing publication is a frustrating challenge and those with unconventional or ambitious approaches can struggle to gain support and acceptance.

“It’s a flawed system,” said David Langer, who is chair of neurosurgery at Lenox Hill Hospital, spent 18 years studying and working at Penn and was Karikó’s student and collaborator.

. . .

Penn wasn’t the only institution to doubt Karikó’s belief in mRNA when many other scientists pursued a different gene-based technology. In a reflection of how radical her ideas were at the time, she had difficulty publishing her research and obtaining big grants—prerequisites for those hoping to get ahead in science and gain academic promotions.

Another reason her relationship with the school frayed: Karikó could antagonize colleagues. In presentations, she often was the first to point out mistakes in their work. Karikó didn’t intend to offend, she just felt the need to call out mistakes, she later said.

For the full story see:

Gregory Zuckerman. “Penn Toasts Winning Scientist After Shunning Her for Years.” The Wall Street Journal (Thursday, Oct. 5, 2023 [sic]): A2.

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

(Note: the online version of the story has the date October 4, 2023 [sic], and has the title “After Shunning Scientist, University of Pennsylvania Celebrates Her Nobel Prize.”)

The source of the Karikó quote in my opening comments is:

Dominique Mosbergen, Peter Loftus and Gregory Zuckerman. “Pair Met With Doubts, Now Win Nobel Prize.” The Wall Street Journal (Tuesday, Oct. 3, 2023 [sic]): A1-A2.

(Note: the online version of the story was updated October 2, 2023 [sic], and has the title “Pioneers of mRNA Find Redemption in Nobel Prize.”)

For more detailed accounts of Karikó’s life, struggles, and research see:

Karikó, Katalin. Breaking Through: My Life in Science. New York: Crown, 2023.

Zuckerman, Gregory. A Shot to Save the World: The inside Story of the Life-or-Death Race for a Covid-19 Vaccine. New York: Portfolio/Penguin, 2021.

Innovative Medical Project Entrepreneur Alan Scott “Coaxed” the F.D.A. to Approve Botox

Even though Alan Scott may have been a “lousy businessman,” he appears nonetheless to still have been an important innovative medical project entrepreneur. (I have not yet read the book discussed in the passages quoted below, but I hope to read it soon. Besides my admiration for innovative project entrepreneurs, an added reason that I am interested in the book is that I have always suffered from esophoria, which is one form of the strabismus that Alan Scott was trying to treat.)

(p. C9) Today botulinum toxin—purified, diluted and known as Botox—nets annual sales in the billions. It is used to treat everything from wrinkles to migraines, yet the pioneer largely responsible for fulfilling Kerner’s prophecy and bringing botulinum into medicine is virtually unknown. He was, it turns out, a laconic Bay Area ophthalmologist named Alan Scott, a self-described “lousy businessman” who barely recouped his own expenses as he coaxed the product to FDA approval.

Eugene Helveston seeks to rescue Scott from oblivion in “Death to Beauty,” a pandemic passion project and labor of love. As an ophthalmologist “of the same era,” Dr. Helveston knew Scott professionally and participated as a researcher in the original clinical trial of botulinum in the mid-1980s. Recognizing that only a few people were still around who could “tell the story firsthand,” Dr. Helveston resolved to document this medical history and corresponded with Scott from June 2021 until Scott’s death six months later, at age 89. The result is an absorbing insider’s account of an exceptional journey.

. . .

Scott was especially interested in strabismus, a disorder characterized by misaligned eyes. The condition was usually treated with surgery, with often disappointing results. Scott began to wonder if strabismus could be treated without surgery by injecting a substance that would weaken a specific eye muscle and thus help restore alignment. It was this line of research that led him to contemplate botulinum, which he requested and received from Schantz in 1972, delivered by the Postal Service in a sealed metal container. Fatefully, he reported promising results in animal models the next year without first filing a patent, which meant that his valuable intellectual property went unprotected.

To enable human testing, Scott submitted an application to the FDA in 1974; the document “lay on some FDA desk for almost four years,” he told Dr. Halversten, before a nudge from a colleague re-engaged the agency. Scott received testing authorization in 1978 and injected the first human subject with a low test dose to evaluate safety. There were no complications, and the trial proceeded.

. . .

Though Botox never gained much traction for the treatment of strabismus, the drug’s other uses lifted it to blockbuster status. Scott received only modest compensation for his foundational work, yet by all accounts he had no regrets. Allergan may have “got all the money,” he said, but “we had all the fun.”

For the full review see:

David A. Shaywitz. “Toning Up With a Toxin.” The Wall Street Journal (Saturday, Dec. 17, 2024): C9.

(Note: ellipses added.)

(Note: the online version of the review has the date February 9, 2024, and has the title “‘Death to Beauty’ Review: The Birth of Botox.”)

The book under review is:

Helveston, Eugene M. Death to Beauty: The Transformative History of Botox. Bloomington, IN: Indiana University Press, 2024.

F.D.A. Should Allow Physicians and Parents the Freedom to Give Preterm Infants Probiotics

Substantial observational evidence shows that the status of a person’s microbiome can have a large effect on the person’s health. We still have a lot to learn about which bacteria are helpful and the details of how they help. But patients must act under uncertainty, or in the case of the preterm infants discussed in the passages quoted below, physicians and parents must act under uncertainty. Given the current evidence and the uncertainty, the F.D.A. is arrogantly wrong to ban probiotics.

(p. A5) For years, hospitals around the world have tried to protect prematurely born babies from life-threatening gut disease by giving them probiotics. Then . . . [in Oct. 2023], American hospitals stopped.

The Food and Drug Administration had linked an infant’s recent death to one of the products. It warned doctors about using them in preterm infants without getting agency permission first, and pushed Abbott Laboratories and another major manufacturer, Infinant Health, to stop selling them.

. . .

Neonatologists in the U.S. and other developed countries have learned to help smaller and smaller babies stay alive. As they treat tinier babies, the medical challenges mount, including a swift-onset disease known as necrotizing enterocolitis, or NEC.

. . .

To help prevent NEC, nearly all neonatal units in Australia and New Zealand give probiotics, as do a majority in several European countries. About 40% in the U.S. did before the FDA’s actions, according to recent surveys and neonatologists’ estimates.

Nearly all of the products consist of live bacteria intended to help create a healthy community of microbes in the gut. Scientists don’t know exactly how they work, but suspect they prevent harmful bacteria from overwhelming the bowels.

. . .

Neonatal units across the U.S. halted use of the probiotics because popular versions were no longer available and the FDA warned doctors against using probiotics for preterm babies outside of clinical trials.

“I was stunned,” said Jennifer Canvasser, who started a NEC patient advocacy group after her infant son died 10 years ago, weakened by the disease. “To think about families having one potential less way to prevent this devastating disease is just concerning.”

Probiotics supporters say the FDA disregarded the evidence favoring probiotics for preterm babies, saying that they likely save hundreds of infants for every one probiotic-caused infection, which can be treated with antibiotics.

An analysis of more than 100 studies involving more than 25,000 premature infants, published . . . [in Oct. 2023] in the journal JAMA Pediatrics, found that probiotics containing multiple strains of bacteria were associated with reduced deaths and NEC.

For the full story see:

Liz Essley Whyte. “Discord Arises Over Treating Preemie Babies.” The Wall Street Journal (Saturday, Nov. 17, 2023 [sic]): A5.

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

(Note: the online version of the story was updated Nov. 16, 2023 [sic], and has the title “Doctors, FDA Fight Over Giving Probiotics to Premature Babies.” The passages quoted above omit the subheadings that appear in the print, but not the online, version of the story.)

The analysis published in JAMA Pediatrics and mentioned above is:

Wang, Yuting, Ivan D. Florez, Rebecca L. Morgan, Farid Foroutan, Yaping Chang, Holly N. Crandon, Dena Zeraatkar, Malgorzata M. Bala, Randi Q. Mao, Brendan Tao, Shaneela Shahid, Xiaoqin Wang, Joseph Beyene, Martin Offringa, Philip M. Sherman, Enas El Gouhary, Gordon H. Guyatt, and Behnam Sadeghirad. “Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis.” JAMA Pediatrics 177, no. 11 (2023): 1158-67.

For a useful discussion of how current medical protocols, especially the over-prescription of antibiotics, harm the microbiome, see chapter 3 of:

Makary, Marty. Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. New York: Bloomsbury Publishing, 2024.

The American Academy of Pediatrics Ignored Early Evidence that Having Infants AVOID Peanuts CAUSES Peanut Allergy

I have praised Marty Makary’s Blind Spots in earlier posts, partly for its compelling examples of where mainstream medicine has failed to adapt to new, strong, sometimes observational evidence. His opening major example is the American Academy of Pediatrics’s long ban on giving peanuts to infants and toddlers. Instead of protecting them from peanut allergy, the ban caused a large increase in peanut allergy. In the essay quoted below, Makary summarizes the peanut example from Blind Spots.

(p. C4) In 1999, researchers at Mount Sinai Hospital estimated the incidence of peanut allergies in children to be 0.6%. But starting in the year 2000, the prevalence began to surge. Doctors began to notice that more children affected had severe allergies.

What had changed wasn’t peanuts but the advice doctors gave to parents about them. The American Academy of Pediatrics (AAP) wanted to respond to public concern by telling parents what they should do to protect their kids from peanut allergies. There was just one problem: Doctors didn’t actually know what precautions, if any, parents should take. Rather than admit that, in the year 2000 the AAP issued a recommendation for children 0 to 3 years old and pregnant and lactating mothers to avoid all peanuts.

. . .

Dr. Gideon Lack, a pediatric allergist and immunologist in London, had a different view. In 2000 he was giving a lecture in Israel on allergies and asked the roughly 200 pediatricians in the audience, “How many of you are seeing kids with a peanut allergy?” Only two or three raised their hands. Back in London, nearly every pediatrician had raised their hand to the same question.

Startled by the discrepancy, he had a eureka moment. Many Israeli infants are fed a peanut-based food called Bamba. To Lack, this was no coincidence, and he quickly assembled researchers in Tel Aviv and Jerusalem to launch a formal study. It found that Jewish children in Israel had one-tenth the rate of peanut allergies compared with Jewish children in the U.K., suggesting that genetic predisposition was not responsible, as the medical establishment had assumed.

Lack and his Israeli colleagues titled their paper “Early Consumption of Peanuts in Infancy Is Associated with a Low Prevalence of Peanut Allergy.” However, the 2008 publication was not enough to uproot groupthink. Avoiding peanuts had been the correct answer on medical school tests and board exams, which were written and administered by the American Board of Pediatrics. For nearly a decade after AAP’s peanut avoidance recommendation, neither the National Institute of Allergy and Infectious Diseases (NIAID) nor other institutions would fund a robust study to evaluate whether the policy was helping or hurting children.

Meanwhile, the more that health officials implored parents to follow the recommendation, the worse peanut allergies got. From 2005 to 2014, the number of children going to the emergency department because of peanut allergies tripled in the U.S. By 2019, a report estimated that 1 in every 18 American children had a peanut allergy. . . .

In a second clinical trial, published in the New England Journal of Medicine in 2015, Lack compared one group of infants who were exposed to peanut butter at 4-11 months of age to another group that had no peanut exposure. He found that early exposure resulted in an 86% reduction in peanut allergies by the time the child reached age 5 compared with children who followed the AAP recommendation.

. . .

When modern medicine issues recommendations based on good scientific studies, it shines. Conversely, when doctors rule by opinion and edict, we have an embarrassing track record. Unfortunately, medical dogma may be more prevalent today than in the past because intolerance for different opinions is on the rise, in medicine as throughout society.

For the full essay see:

Marty Makary. “Who’s Responsible for America’s Peanut Allergy Epidemic?” The Wall Street Journal (Saturday, Sept. 21, 2024): C4.

(Note: the online version of the essay has the date September 19, 2024, and has the title “How Pediatricians Created the Peanut Allergy Epidemic.”)

Makary’s essay is adapted from his book:

Makary, Marty. Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. New York: Bloomsbury Publishing, 2024.

Regulators Wanted to Renege on Promise to Clinical Trial Volunteers Who Got the Placebo

Everyone agrees that those who receive the placebo in a randomized double-blind controlled trial (RCT) are losers in the clinical lottery. The question is whether the epistemic gain from RCTs justifies the pain for the losers? I am not a fan of Fauci, but his proposed solution to the dilemma in the case discussed below seems plausible, if we assume (as I do not) that RCTs are a necessary condition for all actionable medical knowledge and yet we still attempt to treat clinical trial volunteers ethically. My even better solution is to allow all willing volunteers to take the experimental drug, with no-one receiving a placebo. Then use some Bayesian updating technique to gather information from the comparison of results for study participants who volunteered to take the drug, with results for study participants who did not volunteer to take the drug. The study would not be blind, but useful information could be obtained, for instance if no one who takes the drug suffers from the disease, but many who do not take the drug, do suffer from the disease. In that case we have evidence that the drug is effective.

(p. A7) In October [2020], Judith Munz and her husband, Scott Petersen, volunteered for a coronavirus vaccine trial. At a clinic near their home in Phoenix, each got a jab in the arm.

Dr. Petersen, a retired physician, became a little fatigued after his shot, and developed redness and swelling on his arm. But Ms. Munz, a social worker, didn’t notice any change. “As much as I wanted it, I couldn’t find a darned thing,” she said. “It was a nothing burger.”

She knew there was a 50-50 chance that she would get the vaccine, developed by Johnson & Johnson. Judging from her lack of symptoms, she guessed she had received the placebo.

At the time, Ms. Munz thought that anyone who had received the placebo would get the real vaccine as soon as the trial showed it was safe and effective. She looked forward to the peace of mind it would bring. But last month, she was asked to sign a modified consent form indicating that people who got the placebo might have to wait up to two years to get the vaccine, if they got one at all.

Ms. Munz found the form vague, confusing and, most of all, unfair. “You put yourself out there with that risk,” she said. “I am owed that vaccine.”

. . .

But on Wednesday [Dec. 2, 2020], 18 leading vaccine experts — including a top regulator at the Food and Drug Administration — argued that vaccinating placebo groups early would be disastrous for the integrity of the trials. If all of the volunteers who received placebo shots were to suddenly get vaccinated, scientists would no longer be able to compare the health of those who were vaccinated with those who were not.

“If you’re going to prioritize people to get vaccinated, the last people you should vaccinate are those who were in a placebo group in a trial,” said Richard Peto, a medical statistician at the University of Oxford. Mr. Peto and his colleagues laid out their concerns in a new commentary in The New England Journal of Medicine.

. . .

Yet the prospect of giving people something useless in the face of a life-threatening disease has always been fraught. Even Jonas Salk balked at the idea of giving people placebos when researchers designed a trial to test his new polio vaccine in 1953.

“I would feel that every child who is injected with a placebo and becomes paralyzed will do so at my hands,” he complained. The study, Dr. Salk declared, “would make Hippocrates turn over in his grave.”

. . .

Dr. Fauci sketched out one possible way to balance the obligation owed to people who took the placebo against the need for more data from the trials. Vaccine makers could give everyone who got the placebo the vaccine — while also giving everyone who got the vaccine the placebo. None of the trial participants would know which order they got the doses. The trial could therefore continue to be blinded.

. . .

After learning that it may take two years before Johnson & Johnson will provide her with the real vaccine, Ms. Munz, who is 68, is considering trying to get Pfizer or Moderna’s version as soon as she’s eligible thanks to her age.

“I’ll drop out, which I can do, and I’ll get the vaccine,” she said.

Holly Janes, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues are preparing for this kind of erosion. She and her colleagues are now working on statistical methods to squeeze the most insight out of the trials no matter what their fate.

“It won’t be ideal from a purely scientific vantage point, because we lose the direct comparison between vaccine and placebo,” she said. “But we’re trying to strike a balance between doing what some would argue is right for the participants, and maximizing the public health value that comes out of these trials.”

For the full story see:

Carl Zimmer and Noah Weiland. “Should Volunteers Who Got Placebo Be First to Get the Real Thing?” The New York Times (Thursday, December 3, 2020): A7.

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

(Note: the online version of the story was updated Dec. 18, 2020 [sic], and has the title “Many Trial Volunteers Got Placebo Vaccines. Do They Now Deserve the Real Ones?”)

Regulations Discourage Search for Magic Bullet Cures

The so-called “Inflation Reduction Act” mandates that several of the biggest blockbuster drugs must have prices negotiated between Medicare and Pharma firms. As the commentary quoted below suggests, this creates an incentive for Pharma firms to develop many middling drugs rather than a couple of blockbuster drugs. Paul Ehrlich’s “magic bullet” may be impossible, but we will never know if no-one is trying to discover it.creates an

(p. B10) A true home run in the drug industry is when a company develops a mega-blockbuster that transforms its finances for years.

But with Medicare trying to bring costs down by targeting the industry’s most expensive drugs, a portfolio of medium-size moneymakers that can keep your name off the U.S. government’s naughty list can be a wise strategy.

That is at least one reason why big pharma is investing heavily in biotech companies developing antibody-drug conjugates. Known as ADCs, these treatments work like a guided missile by pairing antibodies with toxic agents to fight cancer. In short, they enable a more targeted form of chemotherapy that goes straight into the cancer cells while minimizing harm to healthy cells.

. . .

One reason most ADCs aren’t likely to become mega-blockbusters like Keytruda, a cancer immunotherapy that has earned 35 approvals across 16 types of cancer, is that they aren’t one-size-fits-all drugs. Instead, they are designed to target a specific protein that is expressed on the surface of a cancer cell. That means that each drug is made with an antibody targeting a subset of cancer. There are more than 100 ADCs being tested in humans by pharma and biotech companies.

For the full commentary see:

David Wainer. “Heard on the Street; Drug Industry’s Secret Weapon: ‘Guided Missiles’.” The Wall Street Journal (Friday, Oct. 27, 2023 [sic]): B10.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date October 26, 2023 [sic], and has the title “Heard on the Street; ‘Guided Missile Drugs’ Could Be Big Pharma’s Secret Weapon.”)