Methodology – artdiamondblog.com

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.

Drugs for Dog Longevity May Also Aid Human Longevity

Dogs have long contributed to advances in human medicine. For instance C. Walton Lillehei experimented on dogs to develop his path-breaking human open-heart operations (see the book King of Hearts). What pains me about those dog contributions is that the dogs themselves died in the experiments. In the more recent dog contributions to human medicine, as discussed in the passages quoted below, the dogs themselves have a good chance to benefit as they contribute to human health. I like that a lot better.

(p. A11) In the quest to help people live longer, scientists and companies are turning to dogs.

. . .

Behind the growing enthusiasm is a mix of scientists and entrepreneurs—building on the surging interest from people aiming to live longer. These groups say insights into dog longevity could provide lessons and perhaps eventually treatments that could help people, too.

. . .

On Tuesday [Nov. 28, 2023], a biotech startup that’s hoping to have the first FDA-approved treatment to extend healthy lifespan in dogs, took a step toward that goal. In a letter viewed by The Wall Street Journal, the Food and Drug Administration affirmed that its drug had demonstrated “reasonable expectation of effectiveness.”

The company, called Loyal, still has to complete several more steps before it can market the drug, and it’s only aimed at canines.

. . .

Celine Halioua, chief executive of Loyal, the biotech startup working toward conditional approval of its lifespan drug, says there is a larger aim in addition to helping dogs live healthier for longer. The company has set a possible precedent for other drugs to be approved for lifespan extension, potentially opening a door for other animal—or human—drug companies to follow.

“I think we can both take the opportunity to build better medicines for our dogs and also to better understand these really complex diseases,” says Halioua, whose own 85-pound Rottweiler mix, Della, is nearing the end of her projected lifespan.

The firm’s drug is an injectable that is designed to reduce levels of IGF-1, a hormone that drives cell growth, in large dogs. High blood levels of IGF-1 have been associated with shorter lifespans in some animal and human studies.

The company’s research has indicated that the drug can reduce those hormone levels, but it would still need a large clinical trial demonstrating it can extend dog lifespans in order to achieve full FDA approval. It also needs the agency’s signoff on the drug’s safety and proper manufacturing before getting conditional approval and beginning to sell it, which Loyal hopes to do in 2026.

Still, the FDA nod this week is a promising next step for the field, dog aging researchers say, and will likely drive more interest from biotech and pharmaceutical companies.

“If it is proven that the drug is effective in dogs then there is a higher chance that it will work in the case of humans, too,” says Eniko Kubinyi, a biologist studying dog behavior and cognition with the Budapest-based Family Dog Project.

For the full story see:

Alex Janin. “Secrets of Anti-Aging, Gleaned From Dogs.” The Wall Street Journal (Thursday, Nov. 30, 2023 [sic]): A11.

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

(Note: the online version of the story has the date November 29, 2023 [sic], and has the title “The Clues to Longer Life That Are Coming From Dogs.” The last four paragraphs quoted above appeared in the more detailed online version, but not the print version, of the article. Some of the earlier quoted sentences are quoted in the longer form that appeared in the online version.)

The biography of Lillehei mentioned in my opening comments above is:

Miller, G. Wayne. King of Hearts: The True Story of the Maverick Who Pioneered Open Heart Surgery. New York: Crown, 2000.

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?”)

“More Than 60%” of Medicines Are Based on Chemicals First “Produced by Living Organisms”

Over millennia life (plants, microbes, fungi) developed toxins to protect them from predators. If humans can identify these toxins, they can use them to likewise protect themselves against diseases. Through serendipitous accident and random trial and error, over tens of thousands of years, indigenous peoples discovered and made use of some of these toxins. We should make use of this knowledge even though it is not certified by any randomized double-blind clinical trials performed by highly credentialed academics. Cassandra Quave, author of the essay quoted below, is working to do this, as is Berkeley professor Noah Whiteman, the author of Most Delicious Poison.

(p. C4) My team moved in unison to clip bits of plants, press them into sheets of paper and stuff them into large collection bags. Later, in my research lab at Emory University, we would test their chemical compounds against antibiotic-resistant pathogens. The possibility of developing new drugs from elements of nature such as our leaf clippings is important for everyone, but it’s personal for me; after losing my leg as a child, I nearly died as a result of postsurgical infection.

In recent decades, with the advance of high-tech methods for synthesizing molecules, the search for useful medical compounds from the natural world, especially plants, has faded. Fortunately, just as we’ve started to recognize the limits of artificial synthesis, even newer technology is now helping scientists like me to release more of nature’s medicinal secrets.

Plants have been the source of countless revolutionary medicines since the 19th century. Scientists derived aspirin from the willow tree, for instance, and morphine from opium poppies. They found quinine, the first treatment for malaria, in the bark of the Amazon’s fever tree (and more than a century later, scientists in China found that artemisinin from sweet wormwood was also a powerful anti-malarial agent). Many groundbreaking cancer drugs also came from plants—Taxol from the Pacific yew tree, vincristine from the Madagascar periwinkle.

Microbes found in soil and fungi launched a golden era of advances in antibiotics, starting with the discovery of penicillin in a mold in 1928. By the peak in the 1950s, scientists were isolating a wide range of antimicrobial compounds from microbes found in nature. But such work ended all too soon, as scientists stopped discovering effective new compounds.

Many of the drugs originally drawn from nature are now synthesized in pharmaceutical factories, using the blueprint of their chemical structures. Natural products (that is, chemicals genetically encoded and produced by living organisms) account for more than 60% of the pharmaceuticals that we possess.

Over the past 30 years, however, the focus on nature waned as scientists instead built large chemical libraries filled with tens of thousands of lab-made molecules. One hope was that the next antibiotic breakthrough would emerge from making and testing enough of these synthetic compounds. But that effort has fallen flat: Though other medicines have been developed in the lab, no new registered classes of antibiotics have been discovered since the 1980s.

For the full essay see:

Cassandra Quave. “Hunting for Medicines Hidden in Plants.” The Wall Street Journal (Saturday, November 20, 2021 [sic]): C4.

(Note: the online version of the essay has the same date and title as the print version.)

Quave’s essay is adapted from her book:

Quave, Cassandra Leah. The Plant Hunter: A Scientist’s Quest for Nature’s Next Medicines. New York: Viking, 2021.

The Noah Whiteman book I praise in my introductory comments is:

Whiteman, Noah. Most Delicious Poison: The Story of Nature’s Toxins―from Spices to Vices. New York: Little, Brown Spark, 2023.

“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.

Those Open to the Unexpected Can Benefit from Serendipity

Serendipitous discoveries often involve seeing something unexpected and imagining a use for it. I am currently reading Mary Makary’s Blind Spots. To explain the inertia of the medical establishment, he points out that seeing our expectations contradicted is painful for us; it causes what Leon Festinger called “cognitive dissonance.” Cognitive dissonance causes stress. Most of us minimize the stress by denying or papering over the experiences that contradict expectations. It takes effort, often painful effort, to keep the contradiction in mind. One of my heroes is Oswald Avery, who discovered that the genetic material is DNA. Before he focused on DNA, he worked hard to understand the behavior of the Pneumococcus bacteria that cause pneumonia. Then Fred Griffith showed that only encapsulated Pneumococcus bacteria could cause pneumonia since unencapsulated Pneumococcus can be eliminated by the immune system, and showed further that unencapsulated Pneumococcus could acquire capsules, and become infectious. This transformation of the Pneumococcus contradicted Avery’s expectations, likely causing the him the stress, and the Graves disease, that paralyzed his research for six months (Barry 2005, pp. 421-422). But Avery did not suppress the contradiction. Eventually he pivoted (or if it takes six months I should say ‘eventually he painfully changed direction’) to the research that led to DNA as the genetic material.

(p. A15) Horace Walpole, who coined the term “serendipity” in a 1754 letter, believed that “the best discoveries are made while one is searching for something else,” according to Mr. Pievani. But blind luck, although often important, is not sufficient in itself, as emphasized by Louis Pasteur when he observed that “chance favors the prepared mind.”

“Serendipity” provides a catalog of serendipitous discoveries. . . .

Mr. Pievani offers a useful and informative survey but sometimes layers his material so elaborately as to be off-putting. Early on, for example, we learn that “in 1762, Venetian playwright Carlo Gozzi, the anti-Goldoni who in the same year published the Turandot, which would inspire Giacomo Puccini, brought to the theater a fairy tale, The Deer King, which in the midst of the rococo revived the novella by Khusrau and Armeno, in particular the theme of the transmigration of souls from human to animal.” Huh? Aside from showcasing Mr. Pievani’s extensive learning, such digressions mostly demonstrate his need for a ruthless editor.

“Serendipity,” translated from the Italian by Michael Gerard Kenyon, is most intriguing when it focuses on people with prepared minds who didn’t merely find something they weren’t looking for but were in fact searching for something else when they had a breakthrough.

. . .

In 1928 Fleming, a microbiologist, had been growing Staphylococcus aureus in petri dishes. One day, upon returning from vacation, he noticed that one of the cultures had been accidentally contaminated with a Penicillium mold, which had mysteriously killed the surrounding bacteria. As a military doctor in World War I, Fleming had seen many soldiers die of bacterial infections, and he surmised that maybe this mold would help cure comparable illness.

. . .

. . ., without a prepared mind à la Pasteur, many key discoveries would have been missed. Mr. Pievani makes clear that “if you do not have predictions and expectations in mind, you will never be able to see that an accidental observation is incongruent and therefore potentially a harbinger of serendipity.” The author seeks to encourage what he calls an “ecology of serendipity” that facilitates scientific discovery. He has some suggestions, notably that one should be a “xenophile: love all things strange, all things different, foreign and new, the exceptions, the deviations.”

For the full review see:

Barash, David P. “BOOKSHELF; Progress By Accident.” The Wall Street Journal (Tuesday, Dec. 17, 2024): A15.

(Note: ellipses added.)

(Note: the online version of the review has the date December 16, 2024, and has the title “BOOKSHELF; ‘Serendipity’: Progress by Accident.” In both versions of the article, the names of works of literature and species of bacteria or mold, are italicized.)

The book under review is:

Pievani, Telmo. Serendipity: The Unexpected in Science. Translated by Michael Gerard Kenyon. Cambridge, Mass.: The MIT Press, 2024.

The book by Barry that I reference in my initial comments is:

Barry, John M. The Great Influenza: The Story of the Deadliest Pandemic in History. Revised ed. New York: Penguin Books, 2005.

With Age, Many Cells Contain Cancerous Mutations That Never Develop Into Cancer

Encouraging non-cancerous mutations that compete for resources with cancerous mutations is a novel approach for curing some cancers, but there are many other novel and plausible approaches. Cancer is a complicated and diverse disease; maybe we will eventually see “cancer” as many different diseases. We have too much uncertainty to mandate one centrally planned approach. Plus citizens have the right to keep the money they earn and to choose how to spend that money. We should keep taxation and regulations low so that diverse funders can follow their judgements to fund diverse approaches. [Most of what I just wrote, I also wrote for an earlier entry.]

(p. D3) Cancer is a disease of mutations. Tumor cells are riddled with genetic mutations not found in healthy cells. Scientists estimate that it takes five to 10 key mutations for a healthy cell to become cancerous.

Some of these mutations can be caused by assaults from the environment, such as ultraviolet rays and cigarette smoke. Others arise from harmful molecules produced by the cells themselves. In recent years, researchers have begun taking a closer look at these mutations, to try to understand how they arise in healthy cells, and what causes these cells to later erupt into full-blown cancer.

The research has produced some major surprises. For instance, it turns out that a large portion of the cells in healthy people carry far more mutations than expected, including some mutations thought to be the prime drivers of cancer. These mutations make a cell grow faster than others, raising the question of why full-blown cancer isn’t far more common.

“This is quite a fundamental piece of biology that we were unaware of,” said Inigo Martincorena, a geneticist at the Wellcome Sanger Institute in Cambridge, England.

. . .

Dr. Martincorena and his colleagues reported their findings on Thursday [Oct. 18, 2018] in the journal Science.

By examining the mutations, the researchers were able to rule out external causes for them, like tobacco smoke or alcohol. Instead, the mutations seem to have arisen through ordinary aging. As the cells divided over and over again, their DNA sometimes was damaged. In other words, the rise of these mutations may just be an intrinsic part of getting older.

. . .

The study . . . raised questions about efforts to detect cancer at its earliest stages, when cancer cells are still rare, Dr. Kennedy said: “Just because someone has mutations associated with cancer doesn’t mean actually they have a malignancy.”

Given the abundance of cancer mutations in healthy people, why isn’t cancer more common? Dr. Martincorena speculated that a healthy body may be like an ecosystem: Perhaps clones with different mutations arise in it, compete for available space and resources, and keep each other in check.

If so, fighting cancer might one day be a matter of helping harmless clones outcompete the ones that can lead to deadly tumors.

For the full commentary see:

Zimmer, Carl. “Matter; Delving Into a Cancer Paradox.” The New York Times (Tuesday, October 23, 2018 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Oct. 18, 2018 [sic], and has the title “Matter; Researchers Explore a Cancer Paradox.”)

The academic article in Science co-authored by Martincorena and mentioned above is:

Martincorena, Iñigo, Joanna C. Fowler, Agnieszka Wabik, Andrew R. J. Lawson, Federico Abascal, Michael W. J. Hall, Alex Cagan, Kasumi Murai, Krishnaa Mahbubani, Michael R. Stratton, Rebecca C. Fitzgerald, Penny A. Handford, Peter J. Campbell, Kourosh Saeb-Parsy, and Philip H. Jones. “Somatic Mutant Clones Colonize the Human Esophagus with Age.” Science 362, no. 6417 (Oct. 18, 2018): 911-17.

When a Therapy Fails in a Clinical Trial, Is That the Fault of the Therapy or of the Trial?

When a proposed therapy fails in a clinical trial is that because the therapy can’t work, or is it because the trial itself was flawed? It is far from written in stone how a clinical trial should be set up. Should the therapy be given by pill or intravenously? In what doses? How often, for how long? At what stage of the disease? Because Stage 3 clinical trials are so expensive and difficult to implement, some therapies may have only one shot to succeed. How many therapies that could have helped some people, will never do so, because the researchers had bad luck, or less skill, in implementing the trial? This problem could be reduced the regulatory mandate to requiring only the Stage 1 and Stage 2 clinical trials, that mainly establish safety (as opposed to the much-more-expensive Stage 3 that mainly establishes efficacy). That way researchers who lacked the deep pockets of the researchers discussed in the article quoted below, could still more often afford multiple shots at designing a trial that would succeed at identifying what therapy, applied to which patients, in what modalities, might cure them, or at least lengthen their lives, or reduce their symptoms. Some of the greatest advances in medicine occurred in an environment of quick trial and error, as when medicine has to be precticed on the battlefield of war, or when Emil Freireich improvised new ingredients for his chemo cocktail to cure some children of childhood leukemia or when Freireich’s protégé Vincent DaVita did the same to cure some adults of Hodgkin’s lymphoma. Ideally I would eliminate all mandates, both to enhance liberty, and to speed trial-and-error therapies. But here I suggest eliminating only Stage 3 clinical trials, not because I think that is ideal, but (following Milton Freidman) because I suspect that policy reform may be the best that is politically feasible. We would maximize trial and error adjustments by eliminating all mandated clinical trials. In the vast majority of decisions in life we make judgements without the benefit of a clinical trial. And such judgements usually are effective and improve with experience. [Gary Klein persuasively makes this point through a multitude of examples, in his tour de force Sources of Power.] What is done in life generally, can also be done in medicine in particular, bringing us more cures, faster.

(p. D4) “There is no reason why cancer vaccines would not work if given at the earliest stage,” said Sachet A. Shukla, who directs a cancer vaccine program at MD Anderson Cancer Center. “Cancer vaccines,” he added, “are an idea whose time has come.” (Dr. Shukla owns stock in companies developing cancer vaccines.)

That view is a far cry from where the field was a decade ago, when researchers had all but given up. Studies that would have seemed like a pipe dream are now underway.

“People would have said this is insane,” said Dr. Susan Domchek, the principal investigator of a breast cancer vaccine study at the University of Pennsylvania.

. . .

“We had this trial, 63 patients, Stage 4 cancer. They had failed all therapies,” Dr. Finn said.

. . .

In their initial studies, it became clear to Dr. Finn and her colleagues that the cancers were too far advanced for immunizations to work. After all, she notes, with the exception of rabies, no one vaccinates against an infectious disease in people who are already infected.

“I said, ‘I don’t want to do that again,’” Dr. Finn said. “It is not the vaccines. We have to look at different patients.”

Now, she and her colleague at Pittsburgh, Dr. Robert Schoen, a gastroenterologist, are trying to prevent precancerous colon polyps with a vaccine. But intercepting cancer can be tricky.

They focused on people whose colonoscopies had detected advanced polyps — lumps that can grow in the colon, but only a minority of which turn into cancer. The goal, Dr. Schoen said, was for the vaccine to stimulate the immune system to prevent new polyps.

It worked in mice.

“I said, ‘OK, this is great,’” Dr. Schoen recalled.

But a recently completed study of 102 people at six medical centers randomly assigned to receive the preventive vaccine or a placebo had a different result. All had advanced colon polyps, giving them three times the risk of developing cancer in the next 15 years compared to people with no polyps.

Only a quarter of those who got the vaccine developed an immune response, and there was no significant reduction in the rate of polyp recurrences in the vaccinated group.

“We need to work on getting a better vaccine,” Dr. Schoen said.

. . .

Dr. Domchek said she can envision a future in which people will have blood tests to find cancer cells so early that they do not show up in scans or standard tests.

“To paint a grand future,” she said, “if we knew the tests predicted cancer we could say, ‘Here’s your vaccine.’”

For the full story see:

Gina Kolata. “New Hopes for a Cancer Vaccine.” The New York Times (Tuesday, Oct. 11, 2022 [sic]): D4.

(Note: ellipses added.)

(Note: the online version of the story has the date Oct. 10, 2022 [sic], and has the title “After Giving Up on Cancer Vaccines, Doctors Start to Find Hope.” Where the wording of the versions differs, the passages quoted above follow the online version.)

Gary Klein’s main book that I praise in my initial comments is:

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

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.