Costs and Difficulties of Clinical Trials Delay “Most Promising Experimental Drugs”

(p. A6) As the coronavirus pandemic continues to wreak havoc in the United States and treatments are needed more than ever, clinical trials for some of the most promising experimental drugs are taking longer than expected.

Researchers at a dozen clinical trial sites said that testing delays, staffing shortages, space constraints and reluctant patients were complicating their efforts to test monoclonal antibodies, man-made drugs that mimic the molecular soldiers made by the human immune system.

As a result, once-ambitious deadlines are slipping. The drug maker Regeneron, which previously said it could have emergency doses of its antibody cocktail ready by the end of summer, has shifted to talking about how “initial data” could be available by the end of September [2020].

And Eli Lilly’s chief scientific officer said in June that its antibody treatment might be ready in September, but in an interview this week, he said he now hopes for something before the end of the year.

“Of course, I wish we could go faster — there’s no question about that,” said the Eli Lilly executive, Dr. Daniel Skovronsky. “I guess in my hopes and dreams, we enroll the patients in a week or two, but it’s taking longer than that.”

For the full story, see:

Katie Thomas. “Clinical Trials of Drugs For Virus Are Delayed By a Swamped System.” The New York Times (Saturday, August 15, 2020): A6.

(Note: bracketed year added.)

(Note: the online version of the story has the date Aug. 14, 2020, and has the title “Clinical Trials of Coronavirus Drugs Are Taking Longer Than Expected.”)

Bayesian Updating, Not Clinical Trials, Is Key to Advancing Medical Knowledge

(p. D8) In the early pandemic era, for instance, airborne transmission of Covid-19 was not considered likely, but in early July the World Health Organization, with mounting scientific evidence, conceded that it is a factor, especially indoors. The W.H.O. updated its priors, and changed its advice.

This is the heart of Bayesian analysis, named after Thomas Bayes, an 18th-century Presbyterian minister who did math on the side. It captures uncertainty in terms of probability: Bayes’s theorem, or rule, is a device for rationally updating your prior beliefs and uncertainties based on observed evidence.

. . .

As Marc Lipsitch, an infectious disease epidemiologist at Harvard, noted on Twitter, Bayesian reasoning comes awfully close to his working definition of rationality. “As we learn more, our beliefs should change,” Dr. Lipsitch said in an interview.

. . .

But there is little point in trying to establish fixed numbers, said Natalie Dean, an assistant professor of biostatistics at the University of Florida.

“We should be less focused on finding the single ‘truth’ and more focused on establishing a reasonable range, recognizing that the true value may vary across populations,” Dr. Dean said. “Bayesian analyses allow us to include this variability in a clear way, and then propagate this uncertainty through the model.”

. . .

Joseph Blitzstein, a statistician at Harvard, delves into the utility of Bayesian analysis in his popular course “Statistics 110: Probability.” For a primer, in lecture one, he says: “Math is the logic of certainty, and statistics is the logic of uncertainty. Everyone has uncertainty. If you have 100 percent certainty about everything, there is something wrong with you.”

By the end of lecture four, he arrives at Bayes’s theorem — his favorite theorem because it is mathematically simple yet conceptually powerful.

“Literally, the proof is just one line of algebra,” Dr. Blitzstein said. The theorem essentially reduces to a fraction; it expresses the probability P of some event A happening given the occurrence of another event B.

“Naïvely, you would think, How much could you get from that?” Dr. Blitzstein said. “It turns out to have incredibly deep consequences and to be applicable to just about every field of inquiry” — from finance and genetics to political science and historical studies. The Bayesian approach is applied in analyzing racial disparities in policing (in the assessment of officer decisions to search drivers during a traffic stop) and search-and-rescue operations (the search area narrows as new data is added). Cognitive scientists ask, ‘Is the brain Bayesian?’ Philosophers of science posit that science as a whole is a Bayesian process — as is common sense.

. . .

Even with evidence, revising beliefs isn’t easy. The scientific community struggled to update its priors about the asymptomatic transmission of Covid-19, even when evidence emerged that it is a factor and that masks are a helpful preventive measure. This arguably contributed to the world’s sluggish response to the virus.

. . .

In 1650, Oliver Cromwell, Lord Protector of the Commonwealth of England, wrote in a letter to the Church of Scotland: “I beseech you, in the bowels of Christ, think it possible you may be mistaken.”

In the Bayesian world, Cromwell’s law means you should always “keep a bit back — with a little bit of probability, a little tiny bit — for the fact that you may be wrong,” Dr. Spiegelhalter said. “Then if new evidence comes along that totally contradicts your main prior belief, you can quickly ditch what you thought before and lurch over to that new way of thinking.”

“In other words, keep an open mind,” said Dr. Spiegelhalter. “That’s a very powerful idea. And it doesn’t necessarily have to be done technically or formally; it can just be in the back of your mind as an idea. Call it ‘modeling humility.’ You may be wrong.”

For the full story, see:

Siobhan Roberts. “Thinking Like an Epidemiologist.” The New York Times (Tuesday, August 4, 2020): D8.

(Note: ellipses added.)

(Note: the online version of the story has the same date as the print version, and has the title “How to Think Like an Epidemiologist.”)

“The Concept of Microaggressions” Is “Subjective by Nature”

(p. 25) Scott Lilienfeld, an expert in personality disorders who repeatedly disturbed the order in his own field, questioning the science behind many of psychology’s conceits, popular therapies and prized tools, died on Sept. 30 [2020] at his home in Atlanta.

. . .

He . . . received blowback when he touched a nerve. In 2017, he published a critique of the scientific basis for microaggressions, described as subtle and often unwitting snubs of marginalized groups. (For instance, a white teacher might say to a student of color, “My, this essay is so articulate!”) Dr. Lilienfeld argued that the concept of microaggressions was subjective by nature, difficult to define precisely, and did not take into account the motives of the presumed offender, or the perceptions of the purported victim. What one recipient of the feedback might consider injustice, another might regard as a compliment.

The nasty mail rolled in, from many corners of academia, Dr. Lilienfeld told colleagues.

“There was no one like him in this field,” said Steven Jay Lynn, a psychology professor at Binghamton and a longtime collaborator. “He just had this abiding faith that science could better us, better humankind; he saw his championing as an opportunity to make a difference in the world. He enjoyed stepping into controversial areas, it’s true, but the motives were positive.”

For the full obituary, see:

Benedict Carey. “Scott Lilienfeld, 59, Psychologist Who Questioned Science of Psychology, Dies.” The New York Times, First Section (Sunday, October 18, 2020): 25.

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

(Note: the online version of the obituary has the date Oct. 16, 2018, and has the title “Scott Lilienfeld, Psychologist Who Questioned Psychology, Dies at 59.”)

Expense of Clinical Trials Reduce the Incentive to Re-Purpose Old, Cheap, Off-Patent Vaccines

(p. A5) “Retrospective studies are great and they provide some hints, but there are caveats,” said Dr. Shyam Kottilil, a professor of medicine with the Institute of Human Virology at the University of Maryland School of Medicine. “It’s very difficult to establish causality.”

Interest in the cross-protective effects of vaccines has led to efforts to repurpose old vaccines that may have potential to provide at least transient protection against the coronavirus until a specific vaccine against SARS-CoV-2 is developed and proven safe and effective, he said.

“But nobody knows whether this approach will work unless we test them,” Dr. Kottilil said. “To endorse this, you need to do really good randomized clinical trials.” There is little incentive for private companies to invest in expensive trials because the old vaccines are cheap and off-patent, he added.

For the full story, see:

Roni Caryn Rabin. “Are Past Vaccinations a Shield? It’s Doubtful.” The New York Times (Thursday, July 30, 2020): A5.

(Note: the online version of the story has the date July 29, 2020, and has the title “Old Vaccines May Stop the Coronavirus, Study Hints. Scientists Are Skeptical.”)

Dolly Parton Sings and Donates with “Effective Sympathy”

The above is an “embed” from a YouTube video posted by singer (and English Professor) Ryan Cordell. The lyrics were written by Gretchen McCulloch and the tune is from Dolly Parton’s “Jolene.” The YouTube URL is: https://www.youtube.com/watch?v=cCwNQtnI64I

In my book Openness to Creative Destruction: Sustaining Innovative Dynamism, I write about “effective sympathy” which I describe as “actions taken by sympathetic observers that actually save or improve the lives of those who are suffering” (p. 110). I admire Dolly Parton for donating copies of The Little Engine That Could to poor children. I also admire Dolly Parton for donating a million dollars to help start research on the Moderna vaccine for Covid-19. Dolly Parton knows how to practice effective sympathy.

(p. 12) She wrote “I Will Always Love You” and “Jolene” on the same day and built a theme park around herself. She has given memorable onscreen performances as a wisecracking hairstylist and harassed secretary. She even helped bring about the creation of “Buffy the Vampire Slayer.”

Now, Dolly Parton’s fans are crediting her with saving the world from the coronavirus. It’s an exaggerated, tongue-in-cheek claim, to be sure. But for legions of admirers, Ms. Parton’s donation this spring to Vanderbilt University Medical Center, which worked with the drugmaker Moderna to develop a coronavirus vaccine, was another example of how her generosity and philanthropy have made her one of the world’s most beloved artists.

. . .

“Her money helped us develop the test that we used to first show that the Moderna vaccine was giving people a good immune response that might protect them,” Dr. Denison said on Tuesday.

Ms. Parton told the BBC on Tuesday [November 17, 2020] that she was excited to hear her contribution provided a “little seed money that will hopefully grow into something great and help to heal this world.”

. . .

On Monday [November 16, 2020], after Moderna announced that early trials of the vaccine showed a 94.5 percent effectiveness rate, fans reacted rapturously.

. . .

Ryan Cordell, an associate professor of English at Northeastern University in Boston, filmed himself singing a song about the vaccine to the tune of “Jolene.”

For the full story, see:

Maria Cramer. “Dolly: A Star of Country, a Songwriter, a Virus Hero.” The New York Times, First Section (Sunday, November 22, 2020): 12.

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

(Note: the online version of the story has the date Nov. 17, 2020, and has the title “Dolly Parton: Singer, Songwriter, Pandemic Savior?” The online version says that the title of the New York print version was “Dolly: Country Music Legend, Songwriter, Pandemic Hero” and its page number was 8. The title of my National print version was “Dolly: A Star of Country, a Songwriter, a Virus Hero” and its page number was 12.)

My book mentioned above is:

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

The use of The Little Engine That Could to encourage entrepreneurial perseverance is analyzed in:

Yandle, Bruce. “I Think I Can! Does the Little Engine That Could Matter?” Journal of Private Enterprise 26, no. 2 (Spring 2011): 127-42.

Arthur Ashton’s Serendipitous Invention of Optical Tweezers

(p. B11) Arthur Ashkin, a physicist who was awarded a 2018 Nobel Prize for figuring out how to harness the power of light to trap microscopic objects for closer study, calling his invention optical tweezers, died on Sept. 21 [2020] at his home in Rumson, N.J.

. . .

Dr. Ashkin’s discovery was serendipitous.

In 1966, he was head of the laser research department at Bell Labs, the storied New Jersey laboratory founded by the Bell Telephone Company in 1925, when he went to a scientific conference in Phoenix. There, in a lecture, he heard two researchers discuss something odd that they had found while studying lasers, which had been invented six years earlier: They had noticed that dust particles within the laser beams careened back and forth. They theorized that light pressure might be the cause.

Dr. Ashkin did some calculations and concluded that this was not the cause — it was most likely thermal radiation. But his work reignited a childhood interest in the subject of light pressure.

Light pushes against everything, including people, because it comprises tiny particles called photons. Most of the time the pressure is utterly insignificant; people, for one, feel nothing. But Dr. Ashkin thought that if objects were small enough, a laser might be used to push them around.

. . .

Then, in 1986, he and several colleagues, notably Steven Chu, achieved the first practical application of optical tweezers when they sent a laser through a lens to manipulate microscopic objects. Their results were published in another paper in Physical Review Letters. Dr. Chu began using the tweezers to cool and trap atoms, a breakthrough for which he was awarded a one-third share of the Nobel Prize in Physics in 1997.

Dr. Ashkin, it was clear, was irked that the Nobel committee had not recognized his foundational work in awarding the prize. But he had already begun to use the tweezers for a different purpose: trapping live organisms and biological material.

Other scientists thought this application would not work, as he explained in an interview with the Nobel Institute after he was awarded the prize in 2018.

“They used light to heal wounds, and it was considered to be deadly,” he said. “When I described catching living things with light, people said, ‘Don’t exaggerate, Ashkin.’”

. . .

Dr. Ashkin was awarded one-half the 2018 physics prize, . . . . In so doing he became, at 96, the oldest recipient of a Nobel Prize at the time.

. . .

Dr. Ashkin’s retirement from Bell Labs did not stop him from continuing his research. When he received word of his Nobel Prize, he was working on a project in his basement to improve solar energy collection. Asked if he was going to celebrate, he said: “I am writing a paper right now. I am not about celebrating old stuff.”

For the full obituary, see:

Dylan Loeb McClain. “Arthur Ashkin, 98, Dies; Nobel-Winning Physicist.” The New York Times (Tuesday, September 29, 2020): B11.

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

(Note: the online version of the obituary was updated Oct. 5, 2020, and has the title “Arthur Ashkin, 98, Dies; Nobel Laureate Invented a ‘Tractor Beam’.”)

The essay about Aoyagi mentioned above is:

Severinghaus, John W. “Takuo Aoyagi: Discovery of Pulse Oximetry.” Anesthesia & Analgesia 105, no. 6 (Dec. 2007): S1-S6.

“Slavery Without Private Property”

(p. B11) Yuri Orlov, a Soviet physicist and disillusioned former Communist who publicly held Moscow accountable for failing to protect the rights of dissidents and was imprisoned and exiled for his own apostasy, died on Sunday [September 27, 2020] at his home in Ithaca, N.Y.

. . .

A credulous Communist Party member since college, Professor Orlov began having doubts about the party based on a growing foreboding under Stalin over what he later described as “slavery without private property.” He was further alienated by the subsequent Soviet repression of civil liberties movements in Hungary and what he called the “savage suppressions of workers’ unrest” in Czechoslovakia.

. . .

In 1956, after publicly advocating democratic socialism, Professor Orlov was fired as a research physicist at the Institute of Theoretical and Experimental Physics and expelled from the Communist Party. In 1973, in a letter to Leonid Brezhnev, the general secretary of the party, he denounced the stultifying effect of repression on scientific research and presciently proposed “glasnost,” or openness, long before that word was in common use.

. . .

Professor Orlov was arrested in 1977 and, after a show trial, sentenced to seven years in a labor camp, followed by five years in Siberian exile, for “anti-Soviet agitation and propaganda.”

For the full obituary, see:

Sam Roberts. “Yuri Orlov, Dissident Of Soviet Union Sent Into Exile, Dies at 96.” The New York Times (Friday, October 2, 2020): B11.

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

(Note: the online version of the obituary has the date Oct. 1, 2020, and has the title “Yuri Orlov, Bold Champion of Soviet Dissidents, Dies at 96.”)

Science Is a Process, Not a Fixed Body of Truths

(p. 14) Both writers exemplify the humanity of science: Seager and Johnson laugh, grieve, hope, fail, try, fail and try again. “We started from almost nothing,” Johnson writes about Mars, though she could be talking about pretty much every human endeavor. “We’ve gone careening down blind alleys and taken countless wrong turns, yet somehow, miraculously, the passion, ingenuity and persistence we have brought to the enterprise have moved us toward a truer understanding of another world.”

Why keep searching for life elsewhere when we sometimes seem to have a hard time appreciating it in our own backyard? What does it say about us?

“It says we’re curious,” Seager writes. “It says we’re hopeful. It says we’re capable of wonder and wonderful things.”

For the full review, see:

Anthony Doerr. “Galaxies Far, Far Away.” The New York Times Book Review (Saturday, September 6, 2020): 14.

(Note: ellipses added. In both the print and online versions, “WSJ” and “Mr. Mackey” are bolded, as are the questions asked by Jaewon Kang. The bolding is not visible in the theme used for this blog.)

(Note: the online version of the review has the date Aug. [sic] 18, 2020, and has the title “These Books Transport You to a Galaxy Far, Far Away.”)

The two books under review are:

Johnson, Sarah Stewart. The Sirens of Mars: Searching for Life on Another World. New York: Crown, 2020.

Seager, Sara. The Smallest Lights in the Universe: A Memoir. New York: Crown, 2020.

“Biology’s Many Unanswered Questions”

Unanswered questions in science provide grounds for thinking that future scientific advances may provide grist for the innovation mill. Some argue innovation has slowed because we have picked all the low-hanging fruit. I doubt it. But if so, the fruit can grow back.

(p. C9) The irresistible enthusiasm of “Great Adaptations” couldn’t come at a better time—science is under assault not merely by know-nothing deniers but in how it is taught and presented to the general public. It’s dispensed as a collection of facts, recitations of what past research has uncovered, findings to be understood, which all too often means just “memorized.” By contrast, as Mr. Catania clearly understands, and demonstrates beautifully in his book, science offers adventures in trying to decode the mysteries of the natural world.

This open-minded, openhearted attitude toward biology’s many unanswered questions is the organizing principle of “Great Adaptations”: how to recognize those mysteries, how to go about solving them, and most important, how to appreciate them. In science, working out the solutions to a puzzle inevitably raises new questions in a process not unlike nuclear fission, in which splitting one nucleus generates the energy to split more—except in this case, the energy released isn’t dangerous but illuminating.

For the full review, see:

David P. Barash. “Biology’s Unanswered Questions.” The Wall Street Journal (Saturday, September 5, 2020): C9.

(Note: the online version of the review has the date Sep. 4, 2020, and has the title “‘Great Adaptations’ Review: Survival of the Weirdest.”)

The book under review is:

Catania, Kenneth. Great Adaptations: Star-Nosed Moles, Electric Eels, and Other Tales of Evolution’s Mysteries Solved. Princeton, NJ: Princeton University Press, 2020.

How “Blind” Is a Double-Blind Trial When Volunteers Know the Side-Effects of the Vaccine?

(p. A8) George Washington University had vaccinated 129 people since its share of the trials started. I would be No. 130. Altogether, Moderna planned to enroll 30,000 people in its trial. Half would be given the actual vaccine and half would get the placebo. The protocol called for two shots spaced a month apart.

Finally, it was time for my injection, which is when things got a little weird.

“We have to leave you now, because this is a double-blind study and we are blinded,” Dr. Malkin said. “You’ve been randomized.”

Before I could ask her to translate what she had just said, she was gone, and two nurses arrived with my vaccine. The first nurse left, and the second nurse, Linda Witkin, asked whether I was right-handed or left-handed, then proceeded to inject my right arm.

“Which one are you giving me, the vaccine or the placebo?” I asked. She gave me a look, clearly not pleased with my questioning.

. . .

With the Moderna trial, the side effects reported so far have been typical: fever, chills, muscle and joint soreness.

. . .

The night after my shot, I took my temperature: 97.5. I felt under my arms for glandular swelling and felt only mild joint pain.

. . .

“You all gave me the placebo, didn’t you?” I demanded of Dr. Diemert on Wednesday, during my one-week checkup. “I cannot believe I went through all of this and got the placebo.”

He told me that the actual vaccine shot was more “viscous” than the placebo, which was why neither he nor Dr. Malkin could be in the room when I got it, because they would have been able to easily determine. And so he really couldn’t answer because the double-blind program is meant to protect doctors like him from patients like me. He said I wasn’t to badger Ms. Witkin, if I ever even saw her again. He also said that most people reacted more to the second shot than the first one.

I texted the peanut gallery, “I feel no different.”

For the full story, see:

Helene Cooper. “From Reporting on Ebola to Being a Volunteer in a Covid-19 Vaccine Trial.” The New York Times (Saturday, September 12, 2020): A8.

(Note: ellipses added.)

(Note: the online version of the story has the date Sep. 11, 2020, and has the title “Covering Ebola Didn’t Prepare Me for This: I Volunteered for the Covid-19 Vaccine Trial.”)

Leo Szilard Was “Ever-Resourceful”

I remember Milton Friedman, in an aside during his price theory class at Chicago, telling us that Leo Szilard used to walk up to him as he walked across campus, and articulately raise some issue in economics. Friedman was clearly impressed with the range of Szilard’s mind. My thought was ‘what’s the big deal about this guy Leo Szilard?’ Since then I have learned that he indeed was a big deal, at least for fans of the survival of Western civilization.

(p. 12) Fatefully, the Fermis sailed from Italy the same week that two Berlin radiochemists discovered nuclear fission.

That discovery was totally unexpected. In spring 1939, working at Columbia with the Hungarian physicist Leo Szilard, Fermi set out to answer a crucial question about it. Uranium atoms release a burst of energy when they fission, enough per atom to make a grain of sand visibly jump. But what then? Was there a way to combine those individual fissions, to turn a small burst into a mighty roar?

Szilard, ever-resourceful, acquired hundreds of pounds of black, greasy uranium-oxide powder from a Canadian mining corporation. Fermi and his students packed the powder into pipe-like tin cans and arranged them equally spaced in a circle within a large tank of water mixed with powdered manganese. At the center of the arrangement they placed a neutron source.

Neutrons from the source, slowed down by the water, would penetrate the uranium atoms in the cans and induce fissions. If the fissioning atoms released more neutrons, those “secondary” neutrons would irradiate the manganese. Measuring the radioactivity induced in the manganese would tell Fermi if the fissions were multiplying. If so, then a chain reaction might be possible, one bombarding neutron splitting a uranium atom and releasing two neutrons, those two splitting two other uranium atoms and releasing four, the four releasing eight, and so on in a geometric progression that could potentially produce vast amounts of energy for power — or for an atomic bomb. The experiment worked.

For the full review, see:

Richard Rhodes. “Quantifying the World.” The New York Times Book Review (Sunday, January 28, 2018): 12.

(Note: italics in original.)

(Note: the online version of the review has the date Jan. 24, 2018, and has the title “A Remarkable Man Among Remarkable Men and Women.”)

The book under review is:

Schwartz, David N. The Last Man Who Knew Everything: The Life and Times of Enrico Fermi, Father of the Nuclear Age. New York: Basic Books, 2017.