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.”)

Monty Python’s John Cleese on Creativity and Open Offices

(p. D10) Creativity is almost always: unlearned. Ask young children, “Are you creative?” They’ll all raise a hand. By age 16, none of them will because they’ve had their creativity gently squeezed out of them by those who think conventionally.

. . .

One of the great mistakes is: the open-plan office. If I were starting a business—and this is a great time to reinvent the workplace—I’d give everybody an office. It’s essential you’re not interrupted when you’re working. And you must have lots of rooms for people to meet and play.

For the full interview, see:

Jeff Slate, interviewer. “20 ODD QUESTIONS; John Cleese.” The Wall Street Journal (Saturday, Oct 31, 2020): D10.

(Note: ellipsis added. The questions from the interviewer, before each colon, were bolded in the original.)

(Note: the online version of the interview has the date October 28, 2020, and has the title “20 ODD QUESTIONS; John Cleese on Why Open Offices Are Among History’s Greatest Mistakes.”)

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.

The Son of Jonas Salk Calls Operation Warp Speed “Absolutely Extraordinary”

A screen capture from the Replica Edition of the NYT, p. A4 for Thurs., Nov. 18, 2020.

(p. A4) A 76-year-old man in La Jolla, Calif., says he will get a coronavirus but not the way he got a polio vaccine when he was 9 — lined up in the kitchen next to his two siblings. Their father had sterilized the needles and syringes by boiling them on the stove.

The father was Dr. Jonas Salk, who had developed the vaccine.

. . .

At the time, the vaccine had gone through trials with small numbers of children. A trial with 1.8 million children did not begin until the next year, and the vaccine did not receive approval as safe and effective until a year after that — a timetable that he said made the development of coronavirus vaccine candidates in just months “absolutely extraordinary.” He said he had been concerned about pressure from the Trump administration to have a vaccine ready by Election Day. But he also said the decision to back the development of vaccines through Operation Warp Speed, the federal effort to accelerate vaccine development, “was quite positive.”

For the full story, see:

Barron, James. “Coronavirus Update; ‘l Just Didn’t Feel the Shot’.” The New York Times (Wednesday, November 18, 2020): A4.

(Note: ellipsis added.)

(Note: after considerable time spent searching, I was unable to find this article on the nytimes.com web site. I searched on 11/21/20 for the article that had appeared in-print on 11/18/20. In my experience, it is extremely rare for so recent a print article to be missing from the online web site. So, for documentary purposes, I have reproduced a screen capture of the article from the Replica Edition. (For subscribers to the NYT, The Replica Edition provides an online replica of the print edition for the previous 30 days of issues of the NYT.)

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.

Founder Re-Acquires StubHub

In my book Openness to Creative Destruction: Sustaining Innovative Dynamism, I praise project entrepreneurs for having as their main goal, not wealth or fame, but making a ding in the universe (to use Steve Jobs’s phrase). I also suggest that they are more likely to succeed, in part because they are more likely to stick with the venture they founded. But there may be exceptions to my narrative. Eric Baker sounds like a project entrepreneur who left his start-up because of conflicts with his co-founder, and who now is back in charge.

(p. B4) Eric Baker long envisioned bringing together the two ticketing companies he started.

This week eBay Inc. agreed to sell its StubHub unit, a business Mr. Baker launched nearly two decades ago, to Geneva-based Viagogo Entertainment Inc., the ticketing firm with a large European presence he has been running since 2006.

The $4.05 billion all-cash deal would create a global ticketing juggernaut in the booming business of live events. It would also put StubHub back in the hands of the person who early on saw the opportunity in the legitimate resale of tickets.

. . .

“You had to pay through the nose or find people on the street corner to purchase from,” says Mr. Baker. He felt there had to be a better, more efficient way to find tickets and imagined that could happen online.

He headed to Stanford Graduate School of Business that fall and, together with classmate Jeff Fluhr, started StubHub—then called Liquid Seats—in 2000.

. . .

Mr. Baker and Mr. Fluhr—who was chief executive and had majority ownership of the company—had their differences, and in 2004 Mr. Baker left at the board’s direction, said people familiar with the decision.

. . .

When eBay bought StubHub in 2007, Mr. Baker says he opposed the deal. “It’s rare you have the opportunity to have a business like that,” he says. “To me, you try to hold on to something that’s working.”

For the full story, see:

Anne Steele. “StubHub Acquisition Puts Co-Founder Back in Charge.” The Wall Street Journal (Monday, December 2, 2019): B4.

(Note: ellipses added.)

(Note: the online version of the story has the date November 29, 2019, and has the title “The Tale Behind StubHub’s Sale: How Eric Baker Bought Back the Ticket Seller.”)

My book, mentioned above, is:

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

“Greatness in Science Often Comes From the Well-Prepared Mind Turning a Chance Observation Into a Major Discovery”

(p. 27) Takuo Aoyagi, a Japanese engineer whose pioneering work in the 1970s led to the modern pulse oximeter, a lifesaving device that clips on a finger and shows the level of oxygen in the blood and that has become a critical tool in the fight against the novel coronavirus, died on April 18 [2020] in Tokyo.

. . .

Mr. Aoyagi’s contribution to medical science was built on decades of innovation and invention. In an essay about Mr. Aoyagi, John W. Severinghaus, a professor emeritus of anesthesia at the University of California, San Francisco, wrote in 2007 that Mr. Aoyagi’s “dream” had been to detect oxygen saturation levels without having to draw blood.

. . .

But he soon ran into a problem. Blood does not flow smoothly like an open tap, but pulses through the body irregularly, thus preventing an accurate recording of dye levels. The problem, however, turned out to be an opportunity. By devising a mathematical formula to correct for this “pulsatile noise,” he created a device that measured oxygen levels with greater accuracy than before.

“Greatness in science, often, as here, comes from the well-prepared mind turning a chance observation into a major discovery,” Dr. Severinghaus wrote.

For the full obituary, see:

John Schwartz and Hikari Hida. “Takuo Aoyagi, 84; Invented Medical Device.” The New York Times, First Section (Sunday, May 3, 2020): 27.

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

(Note: the online version of the obituary was updated June 20, 2020, and has the title “Takuo Aoyagi, an Inventor of the Pulse Oximeter, Dies at 84.”)

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.

“Robinson Insisted That Creativity Can Be Taught”

(p. B12) Ken Robinson, a dynamic, influential proponent of stimulating the creativity of students that has too often been squelched by schools in the service of conformity, died on Aug. 21 [2020] at his home in London.

. . .

Mr. Robinson consulted with governments and schools around the world, conducted workshops and wrote books, including “Out of Our Minds: Learning to Be Creative” (2001) and “You, Your Child and School: Navigate Your Way to the Best Education” (2018), with Lou Aronica.

He preached that schools needed not only to broaden their curriculums but also to support teachers as creative professionals and to personalize learning by breaking large classrooms — artificial environments that invite boredom, he said — into small groups.

“Kids will take a chance,” he said in the TED Talk. “If they don’t know, they’ll have a go. Am I right? They’re not frightened of being wrong.” But, he added, “By the time they get to be adults, most kids have lost that capacity.”

Mr. Robinson insisted that creativity can be taught — not through direct instruction, but by giving students opportunities, inspiration, encouragement and mentoring.

The educator Salman Khan said that his popular online website Khan Academy draws on Mr. Robinson’s teachings in part by personalizing curriculums to meet individual students’ needs.

“He opened our eyes to an educational system that isn’t fair to a lot of kids and holds back their potential,” Mr. Khan said in a phone interview. “He helped a lot of educators, including myself, say, ‘Hey, look, this is a time to change.’ ”

For the full obituary, see:

Richard Sandomir. “Ken Robinson, Who Encouraged Schools to Nurture Creativity, Is Dead at 70.” The New York Times (Saturday, Sept. 19, 2020): B12.

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

(Note: the online version of the obituary has the date Sept. 11, 2020, and has the title “Ken Robinson, Who Preached Creativity in Teaching, Dies at 70.”)

The updated third edition of Ken Robinson’s first book mentioned above is:

Robinson, Ken. Out of Our Minds: The Power of Being Creative. New York: Wiley, 2017.

Oligopolists Compete Intensely

(p. B3) The race is on between the world’s largest videogame console makers, this time during a period of heightened demand for at-home entertainment through the coronavirus pandemic.

Sony Corp. SNE 1.45% on Wednesday said two versions of the PlayStation 5 would go on sale in November, one for roughly $400 and another for $500. Both consoles will be sold in a small number of countries including the U.S. and Japan starting Nov. 12 and the rest of the world a week later.

Last week, Microsoft Corp. said it would release two new consoles as well, the Xbox Series X for $499 and the Series S for $299, on Nov. 10.

For the full story, see:

Sarah E. Needleman. “Videogame Rivalry Heats Up.” The Wall Street Journal (Thursday, September 17, 2020): B3.

(Note: bracketed year added.)

(Note: the online version of the story was updated Sep. 16, 2020, and has the title “Sony to Launch Two PlayStation 5 Models This Fall.”)

“The F.D.A. and the Drug Houses Were in Bed Together”

(p. A22) Dr. John S. Najarian, a groundbreaking transplant surgeon who made headlines for taking on difficult cases, and who weathered a different type of headline when he was accused, and then exonerated, of improprieties related to a drug he had developed, died on Aug. 31 in Stillwater, Minn., east of Minneapolis.

. . .

In November 1982, Dr. Najarian performed what may have been his highest-profile surgery. The patient was Jamie Fiske, who became the youngest successful liver transplant recipient when Dr. Najarian performed the operation a few weeks before her first birthday. Her parents had made a widely publicized appeal for a donor.

“They were told that she wouldn’t survive that kind of an operation,” Dr. Najarian said in an oral history recorded in 2011 for the University of Minnesota’s Academic Health Center. “I’m not the kind of guy that takes that lightly. So I told them, ‘If a liver becomes available, we’ll transplant it, and it will work’ — a pretty brash statement, but it did.”

Dr. Najarian’s success with transplants was aided by a drug he developed in 1970, a type of antilymphocyte globulin known as Minnesota ALG, which addressed the biggest problem with early transplants: the rejection of the new organ. He said the drug, which he began using around 1970, gave the Minnesota transplant teams notably better results than other surgical centers were getting with a product offered by a pharmaceutical company.

“Everybody thought we were lying,” Dr. Najarian said, “because we could take patients and we could transplant them, and 65 to 70 percent of them did extremely well, whereas they were lucky to have 50 percent with the commercially available product from Upjohn.”

Other transplant centers began asking for the product, and it turned into a multimillion-dollar business for the university. But in 1992, the Food and Drug Administration, which had approved ALG as an investigational drug but not for interstate sale, stopped the program, and the federal authorities began an investigation. The university turned on Dr. Najarian, pressuring him to resign, and in 1995 he was charged with violating drug safety laws and other crimes.

Dr. Najarian maintained that the case was an attempt by the pharmaceutical industry and its friends in the F.D.A. to squash a successful treatment that was costing drug companies money by besting their products.

“The F.D.A. and the drug houses were in bed together,” he said bluntly in the oral history.

His trial in federal court in St. Paul, Minn., in 1996 provided vindication. Judge Richard Kyle threw out six of the charges, and a jury acquitted him of the other 15. The judge then took the extraordinary step of blasting the F.D.A. and the prosecutors.

“I have some questions as to why we were here at all,” Judge Kyle said.

The F.D.A., he added, “was certainly aware of what was going on, and yet they came in here as a witness to testify that somehow they were hoodwinked by this defendant and his colleagues and other people at the university.”

“We had a program here in Minnesota,” the judge added, “which, for all its problems and shortcomings, was a good program, literally saved thousands of lives.”

For the full obituary, see:

Neil Genzlinger. “John Najarian, 92, Revered Transplant Surgeon Who Took Tough Cases, Dies.” The New York Times (Monday, September 29, 2020): A22.

(Note: ellipsis added.)

(Note: the online version of the obituary was updated Sept. 19, 2020, and has the title “John Najarian, Pioneering Transplant Surgeon, Dies at 92.”)