Entrepreneurship – Page 7 – artdiamondblog.com

Almost $2 TRILLION in Compliance Costs for Biden’s 1,213 New Regs over 10 Years

I am queasy about Trump’s tariffs but hopeful about his deregulation. Besides attacks on freedom of speech, regulations are currently the most binding constraint on innovation and flourishing in the U.S. I hope that the tariffs will be a bargaining ploy that in the long run will result in less protectionist policies for both us and our trading partners. But even if my hope is dashed and higher tariffs become a sustained policy, I believe (but cannot prove) that heavy regulations are the greater evil.

(p. A13) By the time Mr. Biden left office, his administration had issued 1,213 new regulations, according to the American Action Forum. The Washington think tank tracks federal regulations, their cost and added paperwork hours on its Regulation Rodeo website. Mr. Biden’s red tape will result in $1.9 trillion in compliance costs over the first 10 years the new rules are in effect, according to AAF.

By comparison, in Mr. Trump’s first term, his administration issued slightly more regulations—roughly 1,340—but many reduced costs to businesses and consumers. In total, they cost only $64.7 billion, less than 4% of Mr. Biden’s total.

Mr. Biden’s regulatory regime was far more expensive than even Barack Obama’s. Over two terms, the Obama administration issued 2,997 regulations, at a price tag of $870.5 billion. That’s less than 46% of the regulatory cost Mr. Biden racked up in four years.

For the full commentary see:

Karl Rove. “Trump Sets Out to Break Burdensome Rules.” The Wall Street Journal (Thursday, Jan. 23, 2025): A13.

(Note: the online version of the commentary has the date January 22, 2025, and has the same title as the print version.)

Tainted Sulfa Drugs Led Feds to Mandate Drug Safety Tests

Note that the impetus for the creation of mandated drug licensing was an episode of tainted sulfa drugs. The motive of the mandate was to assure safety. The later impetus for the strengthening of mandated drug licensing was the thalidomide episode. Again the motive was to assure safety.

Economists annoyingly emphasize trade-offs. If we stuck to regulation for safety, we could vastly reduce the costs of drug development, allowing more and faster drug innovation.

A case can even be made for doing away with safety regulation. Firms have incentives to produce safe drugs, and private certifying organizations provide information, for instance Consumer Reports. And there are many examples of F.D.A.-approved drugs that turned out to be unsafe (e.g., Vioxx). Mandated safety regulations reduce consumer freedom to choose, and slow the amount and speed of new cures. Mandated efficacy regulations reduce them even more.

(p. C6) Between the late 1930s and the late 1940s, every major class of antibiotics was developed, as William Rosen meticulously recounts in “Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine.” Rosen’s highly informed retelling captures the drama of scientists’ quest, against long odds, to find and produce bacteria-killing drugs—and the egos, ambitions, brilliance and resolve that drove them.

. . .

It is a strength of “Miracle Cure” that Rosen places its many tales of discovery in their larger contexts, explaining for instance the near-complete lack of drug-safety regulation that prevailed when the Tennessee-based S.E. Massengill Co. began selling Elixir Sulfanilamide in October 1937. To make the drug more palatable, the company’s chief chemist had dissolved it, along with raspberry flavoring, in a toxic chemical also used in brake fluid. At least 73 people died. The Federal Food Drug and Cosmetic Act became law the following year. Companies would no longer be able to market new drugs without government licensing. And the government would have to ensure that they were safe.

This book is not for the casual reader. At some points Rosen gets into weeds so thick that only aficionados will find a way through. Still, it’s an important contribution to a still-germane yet fast-receding history. And it’s all the more impressive that Rosen, formerly a book editor and publisher, wrote it as he was battling his own intractable disease. An aggressive cancer took his life in April 2016. He left behind a history worth reading.

For the full review see:

Meredith Wadman. “Medicine’s Age of Wonders.” The Wall Street Journal (Saturday, May 20, 2017 [sic]): C6.

(Note: ellipsis added.)

(Note: the online version of the review has the date May 19, 2017 [sic], and has the same title as the print version.)

The book under review is:

Rosen, William. Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine. New York: Penguin Books, 2018.

Allow Those with Skin in the Game to Help Find Quicker Cures

The New York Times devoted more than two and half full pages to the article that I quote from below. Very very few articles receive that much space. The story is meant to inspire and it does. Linde has a terrible genetic disease, as did her mother and grandmother, as do her two sisters, and as might her two daughters. She is uncredentialled, but determined. She reads scientific articles, gives talks at scientific meetings, creates a foundation to raise funds, and with her sisters gave samples from her skin to create cell lines that can be used for research to find a cure. Linde, both literally and figuratively, has skin in the game.

In the article, victims of the disease wish that there were more clinical trials to test more possible cures. If the price of clinical trials were lower, more of them would be supplied. One way to reduce the price would be for the F.D.A. to only mandate testing for safety, not to mandate testing for efficacy. After all, it was concerns over the safety, not the efficacy, of thalidomide, that first accelerated the F.D.A.’s clinical trial mandates. Testing only for safety (Phase 1 and Phase 2 clinical trials), would hugely reduce the price, resulting ultimately in more and quicker cures.

(p. A1) Linde Jacobs paced back and forth across her bedroom, eyeing the open laptop on the dresser and willing the doctor to appear. Her husband was dropping off their older daughter at school. Their younger daughter was downstairs, occupied by a screen. Linde wanted to be alone when she learned whether she carried the family curse.

Linde’s mother, Allison, had died just four weeks before, after a mutant gene gradually laid waste to her brain. In her 50s, Allison transformed from a joyful family ringleader into an impulsive, deceptive pariah. She drove like a maniac on cul-de-sacs. She pinched strangers, shoplifted craft supplies and stole money from her daughter.

Now, on this morning in September 2021, Linde would find out if she had inherited the same vile genetic mutation.

. . .

The doctor finally popped up on the computer. Wasting no time on pleasantries, she shared her screen and zoomed in on one line of laboratory paperwork: POSITIVE.

. . .

Soon, Linde’s husband, Taylor, pulled into the garage and opened the car door. He could hear her sobbing.

. . .

Linde looked at Taylor. “I don’t want you to feel stuck with me,” she said.

(p. A12) Leaving had never crossed his mind. Allison’s miserable experience, he told Linde, did not have to be hers. “You have all this time,” he said. “Do something about it.”

Even as they spoke, scientists were working on projects that might one day help her. Some had discovered how to cure grave conditions with gene editing. Others were tinkering with patients’ skin cells to test experimental drugs. And pharmaceutical companies were developing new Alzheimer’s therapies, one of which happened to target the rare defect in Linde’s brain.

Linde didn’t know any of that yet. But she decided to take Taylor’s advice. She would use the time she had, somehow, to find influential scientists and make them care about what was happening to her — and what might happen to her girls.

Linde and Taylor scoured the internet for any scrap of hope about treating frontotemporal dementia, or FTD. There was little to read.

Taylor remembered a Netflix documentary about a new way to edit genes. The method, called CRISPR, had cured some children with sickle cell disease. He searched “FTD treatment CRISPR” and found the website of Dr. Claire Clelland, a neurologist at the University of California, San Francisco. She had collected skin cells from patients with FTD, reprogrammed them into neurons and tried to edit the faulty genetic code within.

The website listed a phone number. Taylor called and left a message — a Hail Mary, he figured.

Within a day, Dr. Clelland responded by email. “Happy to help if I can,” she wrote.

. . .

(p. A13) “Could I ask a question?” one young scientist said. How much risk, she wondered, was Linde comfortable taking on an experimental treatment? Editing genes with CRISPR was new, after all, and could come with serious side effects.

“Sign me up, patient zero, sounds good,” Linde said.

“What choice do I have,” she added, “if I don’t want the same future for myself as my mom had, and her mom?”

When she wasn’t working or coaching her daughter’s soccer team, Linde threw herself into the scientific research on MAPT — a niche but growing subfield. The gene provides the instructions for cells to make tau, a protein in the brain.

One day she came across news of a project investigating how tau can go awry. She wrote to the scientist leading the work, Dr. Kenneth Kosik of the University of California, Santa Barbara, describing her family and asking to talk.

Dr. Kosik was sitting in his home office when her note landed in his inbox. “It was the second time in my life that I realized, I’ve got to get back to this person in, like, a nanosecond,” he recalled.

. . .

Dr. Kosik told Linde that an elite group of researchers, known as the Tau Consortium, would gather in Boston in a few months for its annual meeting. Dr. Clelland would be there, as would other “Michael Jordans” in the field. We should try to get you there, he said, so the scientists can be reminded of the human toll of tau-related diseases.

A few weeks later, Linde received an invitation to be the keynote speaker. Jenica and Ashlyn could come, too.

She texted her sisters, “Holy shit.”

One morning in Boston in June 2023, Linde and her sisters got all dolled up, only to arrive in a grand hotel ballroom filled with 100 scientists in oxfords and sneakers.

Dr. Kosik introduced Linde to the members of the Tau Consortium. Too nervous to look anyone in the eye, she stared at a screen showing her slides and read from her prepared remarks.

“You will notice the lack of credentials following my name,” she began. But she said her life had brought her other titles: Caregiver. Jail-Bailer. Carrier. She was the heartbeat, she said, of the cells they studied.

. . .

After the Boston talk, Linde received a flurry of invitations to tell her story. She was interviewed on YouTube by Emma Heming Willis, the wife of the actor Bruce Willis, the most famous person known to have frontotemporal dementia. She came face to face with monkeys that carried MAPT mutations in Madison, Wis. And though she detested the crowds and grime of big cities, she flew to places like Philadelphia and Washington, D.C., to at-(p. A14)tend scientific meetings.

Linde, who by then had moved to River Falls, Wis., always returned home exhausted. But the trips were also fortifying. Learning about the latest research quelled her anxiety — and her husband’s. . . .

During her travels, Linde met other families with MAPT mutations. They were all frustrated by the lack of clinical trials for their genetic glitch, especially because several promising treatments were in the pipeline for other dementia genes. Linde and the others started a global survey of people with MAPT mutations. If an opportunity came along for a clinical trial, they would make it as easy as possible for scientists to find volunteers.

. . .

A few months later, Linde and the group started a nonprofit, called Cure MAPT FTD. They have since found more than 500 people with confirmed or possible MAPT mutations in 10 countries, all of whom have expressed interest in participating in future clinical trials.

In March of this year, Linde got an astonishing offer from Dr. Clelland. Along with collaborators at Washington University and the Neural Stem Cell Institute in New York, she wanted to collect skin cells from Linde and her sisters and turn them into clusters that divide infinitely, known as cell “lines.”

“We propose to make new lines that can be shared with academics and also with industry so that people can do drug screening” and CRISPR projects, Dr. Clelland wrote.

. . .

Based on what happened to Allison and Bev, Linde figures she has at least 10 more years before she starts showing symptoms. But there’s no guarantee; some MAPT carriers begin to change in their 20s. Whenever Linde tells a joke a little too loudly, or has a dulled emotional response to a dramatic event, she worries: Is this tau?

That anxious metronome never shuts off. It compels her to fill any moment of downtime reading the latest study or sending another email. She has spent thousands of dollars and hundreds of unpaid hours on travel. But sometimes, like when she finds herself alone in a hotel room, FaceTiming her daughter about a rough day at school, she questions whether these scientific pursuits are really the best way to run out the clock.

. . .

Dr. Clelland said designing a CRISPR molecule that could precisely excise the MAPT mutation from a cell’s genome was not the hard part. The major unsolved challenge is delivering those molecular scissors into the brain. Still, she and her colleagues at U.C.S.F. have set an ambitious goal of getting MAPT therapy into clinical trials within four years.

For the full story see:

Virginia Hughes. “A Mother’s Race to Beat a Genetic Time Bomb.” The New York Times (Wednesday, December 25, 2024): A1 & A12-A14.

(Note: ellipses added.)

(Note: the online version of the story was updated Jan. 2, 2025, and has the title “Fighting to Avoid Her Mother’s Fate, for Her Daughters’ Sake.” I have omitted a few subhead titles that appear in both the online and print versions.)

At Age 84 Scolnick Has the Passion to Persevere at Curing His Son’s Illness

Many of those with the passion to persevere in overcoming the necessary and unnecessary (regulatory) obstacles to medical innovation, do so because they have a sense of urgency due to skin in the game–they or a relative is directly affected by the disease they are passionate to cure. Dr. Edward Scolnick whose story I quote below, is a great example. In the story, we find another example, Ted Stanley, who donated $100 million to Scolnick because Stanley’s son is also suffering mental illness. And perhaps an indirect example? Rienhoff does not directly have skin in the game, but he is playing a key role because of Scolnick’s passion, and Scolnick’s passion is due to his skin in the game.

If we want more cures we will reduce the unnecessary (regulatory) obstacles so that those with less skin in the game (and so less passion to persevere) will also innovate.

[“Skin in the game” has been emphasized by Taleb in his book with that title.]

(p. A1) Dr. Edward Scolnick figures he needs five, maybe 10 more years to solve one of the brain’s greatest mysteries.

Scolnick, 84 years old, has spent most of the past two decades working to understand and find better ways to treat schizophrenia and bipolar disorder, mental illnesses suffered by tens of millions of people, including his son.

“I know I can crack it,” said Scolnick, a noted drug developer who spent his career plumbing the building blocks of DNA for new treatments.

Long before his latest quest, Scolnick spent 22 years at Merck, mostly as head of the drug giant’s laboratory research. He led development of more than two dozen medicines, including the first approved statin to lower cholesterol, an osteoporosis treatment and an anti-HIV therapy.

. . .

(p. A9) In 2021, Scolnick learned that a group of scientists analyzing DNA from thousands of people with schizophrenia had found mutations in 10 genes that substantially increased the risk of developing the illness. They estimated that a mutation on a single gene, called Setd1a, raised the risk 20-fold.

“It got my blood boiling,” Scolnick said. He began pursuing an emerging class of treatments called LSD1 inhibitors, hoping to develop a new drug. Scolnick enlisted Dr. Hugh Young Rienhoff Jr., who recently developed an LSD1 inhibitor to treat blood disorders.

. . .

Rienhoff anticipates testing a new drug for safety as early as next year, first in animals. He said he saw Scolnick’s passion about fielding a breakthrough treatment but didn’t fully understand why until Scolnick shared about his son’s lifelong struggles with mental illness.

Jason Scolnick, 54, said his doctor has been regularly fine-tuning his medications for bipolar disorder over the years to minimize their debilitating side effects. Using the drugs currently prescribed for schizophrenia or bipolar disorder is like undergoing chemotherapy, he said. “There’s no guarantee it will work and it makes you feel terrible, but the cancer will feel worse or kill you.”

There remains a long road ahead for any new medicine. It takes more than a decade, on average, to get a drug from the research lab through government approvals to patients.

. . .

After leaving Merck, Scolnick was hired in 2004 by the Broad Institute of MIT and Harvard to lead research on psychiatric disorders. He fostered ties with Ted Stanley, a memorabilia entrepreneur whose son also suffered with mental illness. In 2007, Stanley gave $100 million to launch the Stanley Center for Psychiatric Research at the Broad, headed by Scolnick for five years.

. . .

Scolnick and Rienhoff had sat together at a Blackstone dinner years earlier. During the meal, Scolnick shared stories with his table companions about Merck’s development of Crixivan, the anti-HIV drug. “I was hearing a piece of history,” Rienhoff said, “not just HIV history.”

Scolnick became emotional describing how the drug developers, facing various obstacles, wrestled with whether or not to keep going. He pushed for the study to continue, given the urgency. At the time, AIDS was killing tens of thousands of people a year in the U.S.

“I said to Ed, ‘You are thinking like a doctor not a scientist,’” Rienhoff said. “That was the beginning of our relationship.”

. . .

Rienhoff has a team of chemists making and testing compounds at labs in the U.S. and abroad.

“I am optimistic something will come of this,” Rienhoff said. “I can do it, but I wouldn’t have done it if not for Ed. I am, really, doing this in a way for Ed.”

. . .

Biotech company Oryzon Genomics in Spain is developing LSD1 inhibitors for cancer and other conditions. Columbia University researchers tried Oryzon’s drug in mice and found it reversed cognitive impairments caused by the Setd1a genetic mutation connected to schizophrenia. Oryzon is running a small trial in Spain of the LSD1 inhibitor in patients with schizophrenia.

Dr. Joseph Gogos, who led the Columbia research, said it was possible such treatments would be approved for people.

Scolnick is more certain—of both a revolutionary new treatment and his living to witness it.

“Before I die, we will see new medicines, new diagnostics, better outcomes for patients burdened by schizophrenia or bipolar illness,” he said. “I will not be happy to die. But I will die happy that my life helped.”

For the full story see:

Amy Dockser Marcus. “Aging Scientist Races Against Time.” The Wall Street Journal (Friday, Nov. 29, 2024): A1 & A9.

(Note: ellipses added.)

(Note: the online version of the story has the date November 26, 2024, and has the title “A Scientist’s Final Quest Is to Find New Schizophrenia Drugs. Will He Live to See Them?”)

L.E.D. Pioneer Akasaki’s “Perseverance — Sheer Doggedness — Paid Off”

(p. B10) Isamu Akasaki, a Japanese physicist who helped develop blue light-emitting diodes, a breakthrough in the development of LEDs that earned him a Nobel Prize and transformed the way the world is illuminated, died on Thursday [April 1, 2021] in a hospital in Nagoya, Japan. He was 92.

. . .

Bob Johnstone, a technology journalist and the author of “L.E.D.: A History of the Future of Lighting” (2017), said in an email, “The prevailing opinion in the late 1980s was that, because of the number of flaws in the crystal structure of gallium nitride, it would never be possible to make light-emitting diodes from it, so why would you even try?”

Dr. Akasaki, he continued, “was willing to stick at what was almost universally recognized to be a lost cause, working away long after researchers at RCA and other U.S. pioneers of gallium nitride LED technology had given up.”

“Eventually,” Mr. Johnstone said, “his perseverance — sheer doggedness — paid off.”

. . .

Dr. Akasaki was awarded hundreds of patents for his research over the years, and the royalties from his groundbreaking work with Dr. Amano eventually funded the building of a new research institute, the Nagoya University Akasaki Institute, completed in 2006.

. . .

When asked in a 2016 interview with the Electrochemical Society to summarize the philosophy guiding his many years of single-minded research, Dr. Akasaki replied, “No pain, no gain.”

“I say this to younger people: Experience is the best teacher,” he continued. “That is, sometimes there is no royal road to learning.”

For the full obituary see:

Scott Veale. “Isamu Akasaki, 92, Nobel Laureate Whose LED Breakthrough Rippled Around the World.” The New York Times (Wednesday, April 7, 2021 [sic]): B10.

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

(Note: the online version of the obituary has the date April 6, 2021 [sic], and has the title “Isamu Akasaki, 92, Dies; Nobel Winner Lit Up the World With LEDs.”)

The book by Bob Johnstone mentioned above is:

Johnstone, Bob. L.E.D.: A History of the Future of Lighting. Scotts Valley, CA: CreateSpace Independent Publishing Platform, 2017.

Amar Bhidé on Uncertainty

I have not read the latest book by Amar Bhidé, briefly discussed in the passages quoted below, but I have assigned a couple of his earlier books in my Economics of Entrepreneurship and Economics of Technology seminars. Bhidé asks important questions and I like his empirically rich and methodologically pluralist approach to answering them.

(p. R2) “Uncertainty and Enterprise: Venturing Beyond the Known” is a must-read for anyone seeking a roadmap to the bewildering array of new technologies exploding today. Written with considerable charm by the distinguished economist and scholar Amar Bhidé— . . . —the book makes a compelling case that hard facts alone cannot prove or predict whether a new political movement, business idea, technology or TV series will succeed. The author offers a fascinating array of stories, examples and ideas of great thinkers— . . . —rather than relying solely on math or statistics. This book provides a new way of looking not only at risk but, more importantly, at uncertainty in an unpredictable world.

For the full review, see:

Elaine Chao. “12 Months of Reading: Elaine Chao.” The Wall Street Journal (Saturday, December 7, 2024): R2.

(Note: ellipses added.)

(Note: the online version of the review was updated Dec. 6, 2024, and has the title “Who Read What in 2024: Political Voices: Elaine Chao.”)

The book praised by Chao is:

Bhidé, Amar. Uncertainty and Enterprise: Venturing Beyond the Known. New York: Oxford University Press, 2024.

Keep Raging at “the Dying of the Light”

I still remember as an undergraduate at Wabash College reading in our intro psychology textbook of an experiment in which a dog was put in a box. Every time the dog tried to leap out of the box, he received an electric shock. Eventually the electric current was turned off. But the dog never again tried to leap. Are we like the dog, too discouraged by past constraints, so that we are resigned to accept the Biblical limit of “three score and 10” (Psalm 90:10)?

But there is a paradox. Kloc cites an article claiming a very high market value for expanded lifespans. But then where are the voters urgently demanding that medical entrepreneurs be unbound? Where are the citizens demanding that regulators stop mandating Phase 3 clinical trials? Citizens with a sense of urgency can make a difference–see the Act-Up movement in the early years of AIDs. When will they?

(p. 1) The longevity industry is coming off perhaps its best run on record. The expected span of an American life has increased by about three decades since 1900 — to around 78 as of 2023. But for many people, even 78 years just won’t do.

The Methuselah Foundation, a biomedical charity, for example, wants to “make 90 the new 50,” and scientists at one biotechnology firm have argued that, unencumbered by disease, the body could potentially make it all the way to age 150. Even more optimistic estimates put the number closer to 1,000.

Whatever the maximum human life span may be, people appear increasingly determined to find it — in particular men, who are more inclined to favor radically extending life, maybe even indefinitely. Last year, nearly 6,000 studies of longevity made their way onto PubMed, a database of biomedical and life sciences papers; that’s almost five times as many as two decades ago.

Along with the creation of dozens of popular podcasts and a sizable supplement industry, that zeal has led to efforts to preserve organs, search out life-extending diets and even try to reverse aging itself.

. . .

(p. 24) Researchers at Harvard and Oxford recently tried to gauge that interest in the marketplace today. They estimated that the total value of any scientific breakthrough that added another decade to global life expectancy would be worth $367 trillion.

For the full story see:

Joe Kloc. “Gilgamesh, Ponce and the Quest to Live Forever.” The New York Times, First Section (Sunday, January 19, 2025): 1 & 24.

(Note: ellipsis added.)

(Note: the online version of the story has the date Jan. 18, 2025, and has the title “The Centuries-Old, Incredibly Male Quest to Live Forever.”)

When Kloc mentions estimates of possible human lifespan “closer to 1,000” he links to a Scientific American interview with João Pedro de Magalhães, professor of biogerontology at England’s University of Birmingham. João Pedro de Magalhães believes that in principle humans could live to 1,000:

Gifford, Bill. “How Old Can Humans Get?” Scientific American (July 31, 2023). Available from https://www.scientificamerican.com/article/how-old-can-humans-get/.

When Kloc says that some “even try to reverse aging itself” he links to:

Poganik, Jesse R., Bohan Zhang, Gurpreet S. Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T. Lu, Amin Haghani, Tong Gong, Anna M. Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B. Clish, Steve Horvath, James P. White, and Vadim N. Gladyshev. “Biological Age Is Increased by Stress and Restored Upon Recovery.” Cell Metabolism 35, no. 5 (2023): 807-20.

Kloc also links to estimates of the economic value of extending lifespans by one year, and by a decade, as given in:

Scott, Andrew J., Martin Ellison, and David A. Sinclair. “The Economic Value of Targeting Aging.” Nature Aging 1, no. 7 (July 2021): 616-23.

“Rage, rage against the dying of the light” is a line from Dylan Thomas’s poem “Do Not Go Gentle Into That Good Night.”

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.

Ozempic 25 Years Sooner Would Have Saved and Improved Many Lives

Apparently Ozempic had been discovered in the late 1980s and could have been on the market roughly 25 years ago. Pfizer decided that the likely potential revenues were not sufficient to justify the huge costs. But what if the costs had not been so huge? For instance what if we adopted the proposal suggested by Milton Friedman, and advocated by me, to stop mandating hyper-expensive Phase 3 clinical trials to prove efficacy? (The mandates to prove safety through Phase 1 and Phase 2 trials would be retained.) With lower costs, Pfizer might have moved forward. Or if Pfizer had not, some other firm probably would have entered the breach sooner. If Ozempic had been available sooner, by now it would be much cheaper. Many lives would have been saved that have been lost. Other lives would have been healthier and happier.

(p. A26) They called 2023 the year of Ozempic, but it now seems GLP-1 drugs might define an entire decade — or an even longer era. The game-changing drugs, which mimic the hormone GLP-1, offer large benefits for not just diabetes management and especially weight loss but also, apparently, heart and kidney and liver disease, Alzheimer’s and dementia, Parkinson’s and addiction of all kinds. And perhaps because of widespread use of the drugs, the obesity epidemic in America may finally and mercifully be reversing.

But of all the things we learned this year about GLP-1s, the most astonishing could be that the revolution might have started decades earlier. Researchers identified the key breakthrough for GLP-1 drugs nearly 40 years ago, it turns out, long before most Americans had even heard the phrase “obesity epidemic.”

This summer, a former dean of Harvard Medical School, Jeffrey Flier, published a long personal reflection that doubled as an alternate history of what may well be the most spectacular and impactful medical breakthrough of the century so far. In 1987, Flier co-founded a biotech start-up that pursued GLP-1 as a potential treatment for diabetes, not long after it had first been identified by researchers who’d also found that the hormone enhanced insulin secretion in the presence of glucose.

The startup obtained worldwide rights to develop GLP-1 as a metabolic therapy from a group of those researchers, based at Massachusetts General Hospital. They even generated clinical results that suggested it might have promise as a weight-loss drug as well — only to have Pfizer, which had agreed to fund the research, withdraw its support, without providing the researchers with an especially satisfying explanation. Instead, Pfizer told Flier and his partners that the company didn’t believe there would be a market for another injectable diabetes treatment after insulin. Well, Flier tells me, “they were wrong.”

. . .

. . . Flier’s memoir is not just a lament for what might have been. In the aftermath of the pandemic emergency, as citizens and officials alike have embraced a more libertarian attitude toward public health, there’s been a similar drift in the public conversation about drug discovery and development. Operation Warp Speed is often held up as a new model — calls for an Operation Warp Speed 2.0 have been followed by those for an Operation Warp Speed for everything — . . .

Many of the same reformers will complain about all the red tape at the F.D.A. and C.D.C., tallying up huge mortality costs imposed by slow-moving government, arguing for human challenge trials in which individuals volunteer to take untested drugs and be deliberately infected and even talking about the invisible graveyard of unnecessary regulation and delay.

This is all fine and good — there are surely lots of things those agencies can speed up. And in recent years, reformers of various stripes have lobbied some worthy additional proposals into the biomedical zeitgeist — for a system based not on patents but on huge and direct cash prizes for medical breakthroughs, for instance, or one helped along by advance market commitments or benevolent patent extensions. Just last week the researchers Willy Chertman and Ruxandra Tesloianu published “The Case for Clinical Trial Abundance,” an invigorating manifesto for drug development reform.

. . . in focusing on government bureaucracy as the major biomedical bottleneck, we are seeing just one piece of the picture and overlooking what is perhaps the central challenge of research and development — that it is, at present, so complicated that difficulties or bad decisions at any stage can stifle the whole decades-long process, distorting the actual medical and public-health functions of drug development in countless ways.

For the full commentary see:

David Wallace-Wells. “We Could Have Had Ozempic Years Ago.” The New York Times, SundayOpinion Section (Sunday, Jan. 5, 2025): 11.

(Note: ellipses added.)

(Note: the online version of the commentary has the date Dec. 25, 2024, and has the title “Pfizer Stopped Us From Getting Ozempic Decades Ago.”)

Dr. Flier’s published “memoir” mentioned above is:

Flier, Jeffrey S. “Drug Development Failure: How GLP-1 Development Was Abandoned in 1990.” Perspectives in Biology and Medicine 67, no. 3 (Summer 2024): 325-36.

“The Clinical Trial Manifesto” mentioned above is the introductory essay in the compilation referenced below. Another essay that looks promising in the compilation is “Unblocking Human Challenge Trials for Faster Progress.”

Chertman, Willy, and Ruxandra Tesloianu, eds. The Case for Clinical Trial Abundance: A Series of Short Papers Outlining Reform Possibilities for Our Nation’s Clinical Trials. Washington, DC: The Institute for Progress (IFP), 2024.

Welcome Immigrant Innovators

Empirical research by reputable economists at some top schools concludes that although “immigrants represent 16 percent of all US inventors . . . immigrants are responsible for 36% of aggregate innovation, two-thirds of which is due to their innovation externalities on their native-born collaborators” (Bernstein et al. 2022, p. 1). (I have not yet looked carefully at this research, but have looked at other papers by Rebecca Diamond (no relation), finding them important and well-done.)

We should make it easier for innovators to enter the United States and harder for murderers and thieves to enter. And whatever immigration rules we adopt, we should enforce. We are unfair to those who follow our immigration rules if we allow others to enter the United States without following our rules.

Beyond that, I think our rules can be fairly generous, even letting in many non-innovative immigrants, if at the same time we adopt policies that give a probable path forward to current Americans who are among the least well-off. In a working paper that I hope to return to soon, I argue that we can create this path forward by unbinding entrepreneurs so that they can create more and better jobs for the least well-off.

(I thank my former student and current friend Aaron Brown for alerting me to the article on immigration.)

The empirical research on immigrant innovators mentioned above is:

Bernstein, Shai, Rebecca Diamond, Abhisit Jiranaphawiboon, Timothy McQuade, and Beatriz Pousada. “The Contribution of High-Skilled Immigrants to Innovation in the United States.” National Bureau of Economic Research Working Paper #30797, December 2022.

My working paper mentioned above is:

Diamond, Arthur M., Jr. “Robustly Redundant Labor Markets.” Working Paper. 2021.

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.