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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.

A.I. May Create More and Better Jobs

In my Openness book, I made good use of The New Division of Labor book by Levy and Murnane that gave plentiful evidence that the innovative dynamism exemplified by the computer revolution on balance resulted in more and better jobs. The Levy/Murnane book is now over 20 years old, so the skeptical might question whether what was true about computers is also still true about artificial intelligence (A.I.). Now one of the book co-authors, Frank Levy, has co-authored a new working paper in which he answers “yes.” The working paper has recently been summarized by Steve Lohr.

Steve Lohr’s article is:

Steve Lohr. “A.I. Is Poised to Put Midsize Cities on the Map.” The New York Times (Mon., December 30, 2024): B1-B2.

(Note: the online version of the Steve Lohr article has the date Dec. 26, 2024, and has the title “How A.I. Could Reshape the Economic Geography of America.”)

The academic working paper co-authored by Frank Levy, that Lohr summarized in The New York Times article mentioned and cited above is:

Abrahams, Scott, and Frank S. Levy. “Could Savannah Be the Next San Jose? The Downstream Effects of Large Language Models.” In SSRN, June 23, 2024.

The book co-authored by Frank Levy and mentioned in my initial comments is:

Levy, Frank, and Richard J. Murnane. The New Division of Labor: How Computers Are Creating the Next Job Market. Princeton, NJ: Princeton University Press, 2004.

My book mentioned in my initial comments is:

Diamond, Arthur M., Jr. Openness to Creative Destruction: Sustaining Innovative Dynamism. New York: Oxford University Press, 2019.

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.

When Ronald Reagan Needed the Owls of Hogwarts

One of my favorite scenes in the first Harry Potter movie is when an owl tries to deliver to Harry Potter an acceptance letter to Hogwarts. Ever since Voldemort murdered Harry’s parents when he was a baby, Harry has lived under a staircase with the Dursleys (Mrs. Dursley was the sister of Harry’s mother). Mr. Dursley, and the other Dursleys too, do not like Harry, hence his living under a staircase. Mr. Dursley sees the letter to Harry, opens it, and when he realizes the contents tears it up. Then a few other copies arrive and Dursley burns them. It would appear that Harry’s hope of escape is dashed.

But then something wonderful. Countless owls fly toward the Dursley house, each carrying copies of the letter. Acceptance letters start pouring through the front door mail slot, down the chimney, and through every opening in the house. Soon the inside of the Dursley house is buried in acceptance letters. Dursley cannot stop Harry from knowing.

I thought of this scene when I was reading the Wikipedia entry for “Human Events.” Human Events was a smallish weekly readers-digest-type newspaper that my father subscribed to for many years (in the 1960s and 1970s?). Copies of Human Events would always be piled up next to his chair in the living room. Human Events was a contrarian publication presenting conservative/libertarian commentaries on the issues of the day.

The Wikipedia article says that starting in 1961, Ronald Reagan is an avid reader of Human Events. In the 1970s he writes articles that appear in Human Events. When he is president, Reagan’s top aides Baker, Darman, and Deaver do not like what is in Human Events, and try to keep copies of it away from him. When Reagan realizes that his aides are blocking Human Events, he “arranged for multiple copies to be sent to the White House residence every weekend” (Edwards 2011, as quoted in Wikipedia entry on “Human Events“).

Unfortunately for Reagan he does not have a flock of wise owls providing redundant information. But Reagan is his own owl.

Harry could not fire Dursley; I wonder why Reagan did not fire Baker, Darman, and Deaver?

Wikipedia gives the source of the Edwards quote as:

Edwards, Lee. “Reagan’s Newspaper.” URL: http://www.humanevents.com/article.php?id=41609

The Second Arthur Mansfield Diamond Would Be 100 Today

Happy Birthday Dad! He was the second Arthur Mansfield Diamond and would be 100 today.

I think if we adopt the right policies, many of us could live to 100. Too late for Dad, and almost certainly for me.

The first Arthur Mansfield Diamond died in 1933, I think. I was told he played the piano by ear and I saw an article saying that when he was a young man he briefly was a book-keeper for the family vaudeville activities. He looked dapper in a straw hat and knew Knute Rockne of Notre Dame. My Dad was eight when cancer took the first Arthur Mansfield Diamond. My Grandma, with no college degree, raised four children during the Great Depression. Cabbage was nutritious and cheap, so Grandma served a lot of sauerkraut. As an adult Dad hated sauerkraut.

Dad was always reading. He is the only person I ever met who read all three volumes of Solzhenitsyn’s Gulag Archipelago. And he read a conservative reader’s digest weekly (or monthly?) newspaper called Human Events. He was a Republican lawyer in an overwhelmingly Democratic county.

When my brothers and I were young he read aloud to us most of the Oz books, and other books including Atlas Shrugged. Thank you Dad, especially for that.

I wish I had finished my book before he died–he would have read it, argued with me about parts of it, but I think mostly liked it.

Dad was active in Toastmasters, a self-help organization for those who want to improve their public speaking. He rose to become the International President. Their headquarters is near Disneyland. When Dad first joined the Toastmasters board, he spent some time in the park. When he returned from that first trip, I remember his excitement at the then-new attraction, the Tiki Room–seeing what was possible in audio animatronics. Mom and Dad took us to Disneyland and on road trips to most of the U.S.

I remember Dad telling me in his last year that one of his regrets is that he won’t know how things turn out.

Dad was not perfect; neither am I. But I miss him and wish I could still talk with him, and thank him for his wit, his curiosity, and his courage in holding unpopular views when he thought they were right.

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.

Dr. Marty Makary Refuses to Stop Asking Questions

I am almost finished reading Marty Makary’s Blind Spots book that is discussed in the passages quoted below from a column by Pamela Paul. Makary writes with wit and clarity. But the thought-provoking examples are what make the book great. And the thought that the examples provoke is that medicine would progress more quickly to more cures if doctors had greater freedom in what they say, write, research, and prescribe.

Marty Makary has been named by President-Elect Trump to head the Food and Drug Administration (F.D.A.)

(p. A22) You probably know about the surge in childhood peanut allergies. Peanut allergies in American children more than tripled between 1997 and 2008, after doctors told pregnant and lactating women to avoid eating peanuts and parents to avoid feeding them to children under 3. This was based on guidance issued by the American Academy of Pediatrics in 2000.

You probably also know that this guidance, following similar guidance in Britain, turned out to be entirely wrong and, in fact, avoiding peanuts caused many of those allergies in the first place.

. . .

As early as 1998, Gideon Lack, a British pediatric allergist and immunologist, challenged the guidelines, saying they were “not evidence-based.” But for years, many doctors dismissed Dr. Lack’s findings, even calling his studies that introduced peanut butter early to babies unethical.

. . .

Finally, in 2017, following yet another definitive study by Lack, the A.A.P. fully reversed its early position, now telling parents to feed their children peanuts early.

But by then, thousands of parents who conscientiously did what medical authorities told them to do had effectively given their children peanut allergies.

This avoidable tragedy is one of several episodes of medical authorities sticking to erroneous positions despite countervailing evidence that Marty Makary, a surgeon and professor at Johns Hopkins School of Medicine, examines in his new book, “Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health.”

. . .

While these mistakes are appalling, more worrisome are the enduring root causes of those errors. Medical journals and conferences regularly reject presentations and articles that overturn conventional wisdom, even when that wisdom is based on flimsy underlying data. For political or practical reasons consensus is often prized over dissenting opinions.

“We’re seeing science used as political propaganda,” Makary told me when I spoke to him by phone. But, he argues, mistakes can’t be freely corrected or updated unless researchers are encouraged to pursue alternative research.

“Asking questions has become forbidden in some circles,” Makary writes. “But asking questions is not the problem, it’s the solution.”

For the full commentary see:

Pamela Paul. “Why Medicine Still Has Such Blind Spots.” The New York Times (Friday, September 20, 2024): A22.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Sept. 19, 2024, and has the title “The Medical Establishment Closes Ranks, and Patients Feel the Effects.” In the print version the word “caused” is emphasized by italics.)

The book praised in my opening comments and in Pamela Paul’s commentary is:

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

“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.

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.

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.

Some Medical Researchers Seek Patient Input on Execution of Studies

In the story quoted below some medical researchers are seeking patient involvement in studies, but I was disappointed to realize that the involvement is mostly superficial with the aim of getting patient agreement to be part of the study. The researchers in the story still see a big divide between patients and doctors. Doctors see patterns and create hypotheses to be tested. Patients, if they want, can stand by posters, and make minor suggestions on the execution of study design.

I suggest, more ambitiously, that patients sometimes, if allowed, can see patterns and create hypotheses. They have the incentive, the skin in the game. And sometimes they have direct experience on what works and what does not work.

(p. R6) Joel Nowak, a 66-year-old Brooklyn, N.Y., resident with metastatic prostate cancer, knows a lot about cancer research. Over the years, he has contributed blood, saliva and medical information to studies in hopes of helping investigators battle the disease.

But something has nagged at him. Almost always, Mr. Nowak says, investigators want data, “but you never hear from them again.”

Then he was asked to join a new endeavor that is trying to change that—by making participants into partners.

The Metastatic Prostate Cancer Project, launched by the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute in Boston, is trying to give participants a bigger stake in studies by asking them for input, inviting them to events and keeping them updated on progress.

. . .

Patients are . . . invited for a tour of the Broad Institute to see its gene-sequencing machines or to meet and share ideas with researchers, says Nikhil Wagle, director of the umbrella initiative.

Dr. Wagle thinks the approach has led to unusually fast and large enrollment. More than 4,000 people enrolled in the breast-cancer project and over 290 in the angiosarcoma initiative. In just a few weeks, more than 200 signed up for the prostate-cancer study.

. . .

Keeping participants up-to-date is another concern for researchers. It is an issue close to home for Corrie Painter, principal investigator of the angiosarcoma project at the Broad and one of the creators of all three of the institute’s cancer initiatives.

Dr. Painter draws on her experiences as a cancer survivor and research participant in shaping interactions with patients. She was diagnosed with angiosarcoma nearly eight years ago. Dr. Painter says that after her diagnosis, like many patients, she felt frustrated at being treated more “as passive recipients of care rather than part of the process of discovery.”

. . .

Meanwhile, some patients are taking the opportunity to play a larger role in shaping studies. Mr. Nowak, for one, joined a patient advisory council of the prostate-cancer project. Members communicate on videoconferences, email exchanges and in person. During a meeting at the Broad, researchers showed a prototype for the saliva kits that were going to be mailed to patients to collect samples.

The advocates told researchers to take “Metastatic Prostate Cancer Project” off the box. “There are a lot of men who don’t want other people to know they have cancer,” says Mr. Nowak.

For the full story see:

Amy Dockser Marcus. “Researchers Look to Enlist Patients as Partners.” The Wall Street Journal (Monday, Feb. 25, 2018 [sic]): R6.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 25, 2018 [sic], and has the title “Medical Researchers Look to Enlist Patients as Partners.” The last two ellipses above indicate where I omit sentences that appeared in the longer online version, but not in the print version.)

Marcus’s story is related to her book:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.