Category: Science

“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.”)

“Epiphany” on a New Approach to Cure “Half of All Cancers”

Many health experts view immunotherapy as the most promising broad approach for curing cancers. Within the broad immunotherapy approach there are many sub-approaches–distinct approaches on how to activate the immune system against cancer. The article quoted below discusses a new sub-approach.

(p. D4) Within every cancer are molecules that spur deadly, uncontrollable growth. What if scientists could hook those molecules to others that make cells self-destruct? Could the very drivers of a cancer’s survival instead activate the program for its destruction?

That idea came as an epiphany to Dr. Gerald Crabtree, a developmental biologist at Stanford, some years ago during a walk through the redwoods near his home in the Santa Cruz mountains.

“I ran home,” he said, excited by the idea and planning ways to make it work.

Now, in a paper published Wednesday [July 26, 2023] in the journal Nature, Dr. Crabtree, a founder of Shenandoah Therapeutics, which is developing cancer drugs, along with Nathanael S. Gray, a professor of chemical and systems biology at Stanford, and their colleagues report that they have done what he imagined on that walk. While the concept is a long way from a drug that could be given to cancer patients, it could be a target for drug developers in the future.

. . .

In laboratory experiments with cells from a blood cancer, diffuse large B-cell lymphoma, the researchers designed and built molecules that hooked together two proteins: BCL6, a mutated protein that the cancer relies on to aggressively grow and survive, and a normal cell protein that switches on any genes it gets near.

. . .

BCL6, at one end of the dumbbell, guides the molecule toward cell-death genes that are part of every cell’s DNA and are used to get rid of cells that are no longer needed.

. . .

When the dumbbell, guided by BCL6, gets near the cell-death genes, the normal protein on the end of the dumbbell arms those death genes. Unlike other processes in the cell that can be reversed, turning on cell-death genes is irreversible.

. . .

The concept could potentially work for half of all cancers, which have known mutations that result in proteins that drive growth, Dr. Crabtree said. And because the treatment relies on the mutated proteins produced by the cancer cells, it could be extremely specific, sparing healthy cells.

For the full story see:

Gina Kolata. “A Key to Making Cancers Self-Destruct.” The New York Times (Tuesday, August 8, 2023 [sic]): D4.

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

(Note: the online version of the story was updated July 31, 2023 [sic], and has the title “Flipping a Switch and Making Cancers Self-Destruct.” Where the wording of the versions differs, the passages quoted above follow the online version.)

The academic article co-authored by Crabtree in Nature (published in July with an “issue date” of Aug. 10) and mentioned above is:

Gourisankar, Sai, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H. Kim, Zhengnian Li, Wendy Wenderski, Juste M. Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R. Green, Nathanael S. Gray, and Gerald R. Crabtree. “Rewiring Cancer Drivers to Activate Apoptosis.” Nature 620, no. 7973 (Aug. 10, 2023): 417-25.

Will Cancer Die from a Magic Rifle Bullet or From Magic Shotgun Pellets?

We dream of a magic bullet that can cure all cancer. But will all “cancer” continue to be seen as one unified disease, with potentially one common cure? Or will we see many diseases, many causes, and many cures? [The idea of a “magic bullet” against a disease was born from the great Paul Ehrlich who found one of the first effective antibiotics (not to be confused with the the more recent environmentalist Paul Ehrlich who is famous for losing his bet with the great Julian Simon).]

(p. D3) A new study, published [online on] Wednesday [Oct. 2, 2019] in the journal Nature, found that fungi can make their way deep into the pancreas, which sits behind your stomach and secretes digestive enzymes into your small intestine.

. . .

One particular fungus was the most abundant in the pancreas: a genus of Basidiomycota called Malassezia, which is typically found on the skin and scalp of animals and humans, and can cause skin irritation and dandruff.  . . .

The results show that Malassezia was not only abundant in mice that got pancreatic tumors, it was also present in extremely high numbers in samples from pancreatic cancer patients, said Dr. Berk Aykut, a postdoctoral researcher in Dr. Miller’s lab.

. . .

Administering an antifungal drug got rid of the fungi in mice and kept tumors from developing. And when the treated mice again received the yeast, their tumors started growing once more — an indication, Dr. Aykut said, that the fungal cells were driving the tumors’ growth.

. . .

The new study also sheds light on how fungi in the pancreas may drive the growth of tumors. The fungi activate an immune system protein called mannose-binding lectin, which then triggers a cascade of signals known to cause inflammation. When the researchers compromised the ability of the lectin protein to do its job, the cancer stopped progressing and the mice survived for longer.

For the full story see:

Knvul Sheikh. “Fungi May Have a Role In Pancreatic Cancer.” The New York Times (Tuesday, October 8, 2019 [sic]): D3.

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

(Note: the online version of the story has the date Oct. 3, 2019 [sic], and has the title “In the Pancreas, Common Fungi May Drive Cancer.” Where the wording of the versions differs, the passages quoted above follow the more detailed online version.)

The study in Nature mentioned above is:

Aykut, Berk, Smruti Pushalkar, Ruonan Chen, Qianhao Li, Raquel Abengozar, Jacqueline I. Kim, Sorin A. Shadaloey, Dongling Wu, Pamela Preiss, Narendra Verma, Yuqi Guo, Anjana Saxena, Mridula Vardhan, Brian Diskin, Wei Wang, Joshua Leinwand, Emma Kurz, Juan A. Kochen Rossi, Mautin Hundeyin, Constantinos Zambrinis, Xin Li, Deepak Saxena, and George Miller. “The Fungal Mycobiome Promotes Pancreatic Oncogenesis Via Activation of MBL.” Nature 574, no. 7777 (Oct. 10, 2019): 264-67.

When Free People Do Not Volunteer for Clinical Trials, Should Researchers Recruit Prisoners?

On the issue of how to ethically motivate prisoners to volunteer for clinical trails on the efficacy of salt-restricted diets, why not offer wages to the prisoners? Prisoners are already sometimes paid small amounts for other activities, like making license plates. Better yet, take my suggestion with a grain of salt, and settle the dispute with well-done observational studies.

(p. D3) Suppose you wanted to do a study of diet and nutrition, with thousands of participants randomly assigned to follow one meal plan or another for years as their health was monitored?

In the real world, studies like these are nearly impossible. That’s why there remain so many unanswered questions about what’s best for people to eat. And one of the biggest of those mysteries concerns salt and its relationship to health.

But now a group of eminent researchers, including the former head of the Food and Drug Administration, has suggested a way to resolve science’s so-called salt wars. They want to conduct an immense trial of salt intake with incarcerated inmates, whose diets could be tightly controlled.

The researchers, who recently proposed the idea in the journal Hypertension, say they are not only completely serious — they are optimistic it will happen.

. . .

Dr. Daniel W. Jones, a professor of medicine and physiology at the University of Mississippi School of Medicine and former president of the American Heart Association, was alarmed by the bitter arguments and increasingly personal disputes between researchers who disagree about salt.

So he invited senior medical scientists on both sides of the debate to meet in Jackson, Miss., to figure out how to settle their differences.

. . .

So suppose you do the study in prisons, said Dr. Jones. Is the research supposed to benefit the prisoners or just the population in general? If the prisoners would not benefit, the study would be unethical.

People who are not incarcerated can choose how much sodium they consume, but prisoners cannot — they eat whatever the facility provides. If there is uncertainty about the ideal amount of sodium, the experts concluded, prisoners would benefit from a study that settled the matter.

. . .

Dr. Macklin, in a telephone interview, also said many prisoners would be happy to jump in. She has taught in a maximum security facility and has studied the ethics of doing research in prisons.

“They would say they want to give back to society,” Dr. Macklin said.

. . .

Prison administrators have told Dr. Jones they would be willing to consider a proposal for a randomized trial of salt.

For the full story see:

Gina Kolata. “Looking to Prison for a Health Study.” The New York Times (Tuesday, June 5, 2018 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the story has the date June 4, 2018 [sic], and has the title “The Ideal Subjects for a Salt Study? Maybe Prisoners.”)

The academic article co-authored by Dr. Jones that proposes a randomized double-blind clinical trial (RCT) in prisons is:

Jones, Daniel W., Friedrich C. Luft, Paul K. Whelton, Michael H. Alderman, John E. Hall, Eric D. Peterson, Robert M. Califf, and David A. McCarron. “Can We End the Salt Wars with a Randomized Clinical Trial in a Controlled Environment?” Hypertension 72, no. 1 (July 2018): 10-11.

If Immortality Does Not Violate the Laws of Physics, Entrepreneurs Can Achieve It

The late Nobel-Prize-winning physicist and idiosyncratic Richard Feynman also said something similar to the quote attributed to Arram Sabeti below.

I do not believe that Feynman was explicitly named, or had any lines, in the movie “Opennheimer,” but you can see his character in the background of one scene playing the bongo drums. Perhaps he was eccentric, but I liked his views on methodology and his unpretentious, optimistic, and straightforward spirit.

(p. 9) As the longevity entrepreneur Arram Sabeti told The New Yorker: “The proposition that we can live forever is obvious. It doesn’t violate the laws of physics, so we can achieve it.”

For the full commentary see:

Dara Horn. “The Men Who Want to Live Forever.” The New York Times, SundayReview Section (Sunday, January 28, 2018 [sic]): 9.

(Note: the online version of the commentary has the date Jan. 25, 2018 [sic], and has the same title as the print version.)