Category: Economics of Technology

“A.I.s Are Overly Complicated, Patched-Together Rube Goldberg Machines Full of Ad-Hoc Solutions”

A.I. can be a useful tool for searching and summarizing the current state of consensus knowledge. But I am highly dubious that it will ever be able to make the breakthrough leaps that some humans are sometimes able to make. And I am somewhat dubious that it will ever be able to make the resilient pivots that all of us must sometimes make in the face of new and unexpected challenges.

(p. B2) In a series of recent essays, [Melanie] Mitchell argued that a growing body of work shows that it seems possible models develop gigantic “bags of heuristics,” rather than create more efficient mental models of situations and then reasoning through the tasks at hand. (“Heuristic” is a fancy word for a problem-solving shortcut.)

When Keyon Vafa, an AI researcher at Harvard University, first heard the “bag of heuristics” theory, “I feel like it unlocked something for me,” he says. “This is exactly the thing that we’re trying to describe.”

Vafa’s own research was an effort to see what kind of mental map an AI builds when it’s trained on millions of turn-by-turn directions like what you would see on Google Maps. Vafa and his colleagues used as source material Manhattan’s dense network of streets and avenues.

The result did not look anything like a street map of Manhattan. Close inspection revealed the AI had inferred all kinds of impossible maneuvers—routes that leapt over Central Park, or traveled diagonally for many blocks. Yet the resulting model managed to give usable turn-by-turn directions between any two points in the borough with 99% accuracy.

Even though its topsy-turvy map would drive any motorist mad, the model had essentially learned separate rules for navigating in a multitude of situations, from every possible starting point, Vafa says.

The vast “brains” of AIs, paired with unprecedented processing power, allow them to learn how to solve problems in a messy way which would be impossible for a person.

. . .

. . ., today’s AIs are overly complicated, patched-together Rube Goldberg machines full of ad-hoc solutions for answering our prompts. Understanding that these systems are long lists of cobbled-together rules of thumb could go a long way to explaining why they struggle when they’re asked to do things even a little bit outside their training, says Vafa. When his team blocked just 1% of the virtual Manhattan’s roads, forcing the AI to navigate around detours, its performance plummeted.

This illustrates a big difference between today’s AIs and people, he adds. A person might not be able to recite turn-by-turn directions around New York City with 99% accuracy, but they’d be mentally flexible enough to avoid a bit of roadwork.

For the full commentary see:

Christopher Mims. “We Now Know How AI ‘Thinks.’ It Isn’t Thinking at All.” The Wall Street Journal (Saturday, April 26, 2025): B2.

(Note: ellipses added.)

(Note: the online version of the commentary has the date April 25, 2025, and has the title “We Now Know How AI ‘Thinks’—and It’s Barely Thinking at All.”)

A conference draft of the paper that Vafa co-authored on A.I.’s mental map of Manhattan is:

Vafa, Keyon, Justin Y. Chen, Ashesh Rambachan, Jon Kleinberg, and Sendhil Mullainathan. “Evaluating the World Model Implicit in a Generative Model.” In 38th Conference on Neural Information Processing Systems (NeurIPS). Vancouver, BC, Canada, Dec. 2024.

Girls Who Are Skilled in Both STEM and Non-STEM Fields, Usually Prefer Non-STEM Fields

Gender discrimination is not the only explanation for there being more men than women in STEM jobs, according to the research summarized in the passages quoted below.

(p. C3) Scores of surveys over the last 50 years show that women tend to be more interested in careers that involve working with other people while men prefer jobs that involve manipulating objects, whether it is a hammer or a computer. These leanings can be seen in the lab, too. Studies published in the Personality and Social Psychology Bulletin in 2016, for example, found that women were more responsive to pictures of people, while men were more responsive to pictures of things.

Consistent with what men and women say they want, the STEM fields with more men, such as engineering and computer science, focus on objects while those with more women, such as psychology and biomedicine, focus on people.

Given the push to get more people—and especially more girls—interested in STEM, it is worth noting that talented students of both sexes tend to avoid a career in math or science if they can pursue something else. STEM jobs aren’t for everyone, regardless of how lucrative they may be.

A study of more than 70,000 high-school students in Greece, published in the Journal of Human Resources in 2024, found that girls on average outperformed boys in both STEM and non-STEM subjects but rarely pursued STEM in college if they were just as strong in other things. A study of middle-aged adults who had been precocious in math as teens, published in the journal Psychological Science in 2014, found that only around a quarter of the men were working in STEM and IT.

Large-scale studies around the world show that women are generally more likely than men to have skills in non-STEM areas, while men who are strong in math and science are often less skilled elsewhere. But while everyone seems to be concerned about whether girls are performing well in STEM classes, no one seems all that troubled by the fact that boys are consistently underperforming in reading and writing.

For the full essay see:

Hippel, William von. “Why Are Girls Less Likely to Become Scientists?” The Wall Street Journal (Saturday, March 8, 2025): C3.

(Note: the online version of the essay has the date March 6, 2025, and has the same title as the print version.)

Hippel’s essay, quoted above, is adapted from his book:

Hippel, William von. The Social Paradox: Autonomy, Connection, and Why We Need Both to Find Happiness. New York: Harper, 2025.

The academic study published in the Journal of Human Resources and mentioned above is:

Goulas, Sofoklis, Silvia Griselda, and Rigissa Megalokonomou. “Comparative Advantage and Gender Gap in Stem.” Journal of Human Resources 59, no. 6 (Nov. 2024): 1937-80.

Vinyl LP Records Have Been Mostly Replaced, but in Kansas Not Completely Destroyed

In my Openness book, I argue that Schumpeter’s phrase “creative destruction” misleads by overemphasizing the extent of destruction in the process of breakthrough innovation, so I prefer to call the process “innovative dynamism.” A new innovation is often better than the old in many, but not all, traits. A minority of people who put heavy weight on the traits where the old product is better, will still prefer the old product. If the minority is large enough, and willing to pay enough for their preference, then there will be enough demand for the old product to remain in production, rather than be fully replaced (i.e., destroyed).

Illustrating my point, The New York Times ran two full pages on Chad Kassem, a Kansas entrepreneur who is working hard, with some success, at making higher quality vinyl LP records. He has 114 employees and annual revenue of over $1 million.

He is even introducing incremental innovations to the old product: (p. 6) “Kassem hired veterans of the record-making business and indulged their ideas for modernizing a process that (p. 7) had barely changed since the 1970s. Among other innovations, they introduced computerized controls and found ways to regulate the fluctuating temperature of vinyl in the presses.”

The New York Times article is:

Ben Sisario. “In a Digital World, Pursuing an Ideal Of Perfect Vinyl.” The New York Times, Arts&Leisure Section (Sun., March 9, 2025): 6-7.

(Note: the online version of The New York Times article on the resilience of vinyl was updated March 7, 2025, and has the title “The Wizard of Vinyl Is in Kansas.”)

My book mentioned in my initial comments is:

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

“If She Ever Had a Clever Thought, It Died Alone and Afraid”

I still smile whenever I see a Tesla Cybertruck. Boldly audacious–its mere existence gives me hope for the future. If I could charge its battery as fast as I can fill a tank of gas, I would buy one tomorrow. I still worry that Musk will implode or cave. But right now he looks like a genuine hero, defending free speech by buying Twitter, taking on the deep state by creating DOGE, solving the engineering challenges to make the dream of Mars a reality!

(p. B1) When Jennifer Trebb first pulled into her driveway two years ago with her sleek Tesla Model Y, it was — as she put it — “kind of like a ‘Back to the Future’ moment.”

She was helping the environment, she said, but driving a Tesla also had cachet. “It was definitely a little bit of a cool moment to have something that was innovative and different,” she said.

But Ms. Trebb recently made a U-turn, joining the ranks of Tesla owners in the United States and overseas — some well known, including the singer Sheryl Crow — who are selling their vehicles because the values and politics of the company’s billionaire chief executive, Elon Musk, are alienating them, they say.

. . .

(p. B6) In the United States, perhaps the most notable rebuke of the car brand was lodged by Ms. Crow, the singer-songwriter, who posted an Instagram video in February [2025] showing her waving goodbye as her electric vehicle was driven away on a flatbed truck.

. . .

In an appearance with Sean Hannity on Fox News, Senator John Kennedy, Republican of Louisiana, mocked Ms. Crow’s protest.

“I think she means well, but if she ever had a clever thought, it died alone and afraid,” Mr. Kennedy said.

For the full story see:

Neil Vigdor. “Tesla for Sale: Buyer’s Remorse Sets In For E.V. Owners Who’ve Soured on Musk.” The New York Times (Friday, March 7, 2025): B1 & B6.

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

(Note: the online version of the story was updated March 5, 2025, and has the title “Tesla for Sale: Buyer’s Remorse Sinks In for Elon Musk’s E.V.-Owning Critics.”)

Pfizer Waited Until Just After Trump Lost 2020 Election to Announce Success of Trump’s “Operation Warp Speed”

I have been suspicious of the timing of Pfizer’s announcement of the efficacy of their vaccine. They announced the efficacy the day after Joe Biden was proclaimed the winner of the election. They deny the obvious inference. The denial could be true, or they could be counting on our gullibility.

I remain suspicious.

(p. A3) Soon after President Trump won the presidential election in November [2024], British drugmaker GSK brought an unusual claim to federal prosecutors in Manhattan, according to people familiar with the matter.

A senior GSK scientist, who formerly worked at rival Pfizer, had told GSK colleagues that Pfizer delayed announcing the success of its Covid vaccine in 2020 until after that year’s election.

. . .

Over the past year, Pfizer executives including Chief Executive Albert Bourla have sought to build a relationship with Trump, . . .

. . .

During the development of Pfizer’s vaccine, Bourla aggressively pushed his employees to develop the vaccine and initially had wanted the vaccine done by October [2020]. He gave similar timelines publicly, telling the “Today” show that the company would know if it worked by October [2020].

. . .

Pfizer filmed and broadcast the moment executives learned the results from Pfizer’s senior scientists, on Nov. 8 [2020].

By then, Trump had lost the election. Joe Biden was declared the winner of the contest on Nov. 7 [2020]. Two days later, Pfizer said an early analysis showed its vaccine to work safely in protecting people from Covid-19.

Just after midnight on Nov. 10, [2020] Trump posted on social media: “As I have long said, @Pfizer and the others would only announce a Vaccine after the Election, because they didn’t have the courage to do it before.”

For the full story see:

Josh Dawsey, Gregory Zuckerman, and Jared S. Hopkins. “Tip on Pfizer Vaccine Timing Is Probed.” The Wall Street Journal (Thurs., March 27, 2025): A3.

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

(Note: the online version of the story was updated March 26, 2025, and has the title “U.S. Prosecutors Probe Tip About Timing of Pfizer Vaccine.”)

U.S. Shipbuilding Industry’s Obsolescence of Physical and Human Capital Threatens Timely Revival of Navy

I have always opposed every form of protectionism. But at the recent APEE meetings in Guatemala City my friend Young Back Choi suggested that there might be circumstances when protectionist policy is justified. One circumstance in particular gives me pause for thought. If a technology is important for national defense, arguably the most important justified function of government, then it might be justified if necessary to maintain U.S. access to a key defense technology. For instance, a recent WSJ article, quoted below, suggests that the U.S. capacity to quickly and efficiently build naval ships has been compromised by the attrition of the U.S. shipbuilding industry.

I believe further thought and research is justified.

(p. A10) The Navy complains U.S. shipyards don’t invest enough in staff and equipment.

McKinsey analysts in a recent report on U.S. shipyards found equipment, including metal casting machines, cranes and transport systems, that was decades old, some harking back to before WW2.

The report said equipment broke down, causing delays to contracts. In some cases, it was so old that replacement parts had to be fabricated from scratch because they were no longer commercially available.

Some shipbuilding executives said European naval yards typically have more modern equipment than those in America.

Some investments have made improvements. In the so-called panel-line at Fincantieri’s Wisconsin yard, where major ship sections are joined together, the addition of robotic welders means that there are now six workers as opposed to the 24 previously needed.

That is important because the U.S. industry has a dearth of experienced older shipyard workers—with the skills necessary for the complex fabrications. A third of workers in Fincantieri’s U.S. shipyard are over 50, compared with almost 40% in Italy. Last year, the Navy blamed inexperienced new hands at a Huntington Ingalls Industries shipyard in Virginia for faulty welding on 26 vessels.

For the full story see:

MacDonald, Alistair, and Gordon Lubold. “A Warship Shows Why China Is Challenging the U.S. Navy.” The Wall Street Journal (Sat., March 22, 2025): A1 & A10.

(Note: the online version of the story has the date March 20, 2025, and has the title “The Warship That Shows Why the U.S. Navy Is Falling Behind China.”)

Healthcare Innovations Can Be Effective AND Cheap

Many are resigned to accept our current mess of a healthcare system because they fear that if the system was changed into a fully free market system they would not be able to afford anything approaching their current level of healthcare. But they do not understand what would change. If patients paid for their own healthcare there would be competition to provide cheaper healthcare services to the many. Henry Ford got rich finding ways to make cars better and cheaper. Bill Gates got rich mainly by making adequate operating systems cheaper.

If we made healthcare a free market, then healthcare would find its Henry Ford and Bill Gates. If patients directly paid for healthcare, then healtcare services would be more consumer oriented–for instance the value of patients’ time would be respected. Medical entrepreneurs would compete to bring us more cures and cheaper cures.

The problem is not that we are “fixated on profits” as is suggested in the last paragraph quoted below. The problem is that our non-market healthcare system creates perverse incentives and perverse regulatory constraints, so that simple frugal innovations are not rewarded.

[Below I first quote a few passages from The New York Times obituary of Cash, and then from The Wall Street Journal obituary of Cash.]

(p. A21) Richard A. Cash, who as a young public-health researcher in South Asia in the late 1960s showed that a simple cocktail of salt, sugar and clean water could check the ravages of cholera and other diarrhea-inducing diseases, an innovation that has saved an estimated 50 million lives, died on Oct. 22 at his home in Cambridge, Mass. He was 83.

. . .

Dr. Cash, the son of a doctor, arrived in East Pakistan, today Bangladesh, in 1967 as part of a project through the U.S. Public Health Service. There he worked with another young American doctor, David Nalin, to respond to a cholera outbreak outside the capital, Dhaka.

The two had already been researching a simple oral rehydration therapy and knew of other, previous efforts, all of which had failed. But they believed that the therapy held promise, especially in the face of mounting deaths.

They realized that a main problem was volume: Past efforts had resulted in too little or too much hydration. Dr. Cash and Dr. Nalin conceived a trial in which they carefully measured the amount of liquid lost and replaced it with the same amount, mixed with salt and sugar to facilitate absorption.

They divided 29 patients into three groups, with one group receiving an IV drip, another an oral treatment through a tube, and the third an oral treatment by drinking from a cup.

Other doctors and nurses found their experiment bizarre and tried to stop them. But Dr. Cash and Dr. Nalin persisted, splitting the work between them in two 12-hour shifts, to ensure the integrity of the trial.

The results were definitive: Only three of the tubed patients — and only two who drank the solution — needed additional IV treatment.

. . .

“We’re enamored by high technology,” he said at the Council on Foreign Relations. “And we’re not in love with low-tech. Low-tech is always seen in our eyes as second-class. Why would you do this, when you could do that? And I would argue just the opposite.”

For the full obituary from The New York Times that is quoted above, see:

Clay Risen. “Richard A. Cash, 83, Who Saved Millions From Dehydration, Dies.” The New York Times (Monday, November 4, 2024): A21.

(Note: ellipses added.)

(Note: the online version of the obituary has the date Nov. 2, 2024, and has the title “Richard A. Cash, Who Saved Millions From Dehydration, Dies at 83.”)

(p. C6) Half a liter of water, plus a pinch of salt and a fistful of sugar. As scientific insights go, it can’t compare to the intricate equations developed to split the atom or map the planets’ paths. But its simplicity was crucial to its monumental impact.

That simple solution—the cornerstone of Oral Rehydration Therapy, or ORT—has proved extraordinary in staving off and reversing the devastating consequences of dehydration caused by cholera and other diarrheal diseases, saving tens of millions of lives since its development nearly six decades ago. In 1978, an editorial in the Lancet called ORT “potentially the most important medical advance of the century.”

. . .

Cash saw this ethos of simplicity and accessibility as instructive for a western medical system that’s infatuated with high-tech solutions, dismissive of low-tech ones and fixated on profits—and where, consequently, an overnight stay in the hospital for dehydration can result in a four-figure bill. “A solution that can’t be applied,” he told Harvard Magazine, “is really no solution at all.”

For the full obituary from The Wall Street Journal that is quoted immediately above, see:

Jon Mooallem. “A Doctor Whose Simple Treatment Prevented Millions Of Cholera Deaths.” The Wall Street Journal (Saturday, Nov. 9, 2024): C6.

(Note: ellipsis added.)

(Note: the online version of the obituary has the date November 7, 2024, and has the title “Richard Cash, Whose Rehydration Therapy Saved Millions of Lives, Dies at 83.”)

Musk’s Defense of Free Speech Leads an E.V. Hater to Become a Tesla Cybertruck Lover

I admire Elon Musk’s energy, his ability to focus his mind in spite of distractions, and his ambitious entrepreneurship. The kid in me who got up early to watch Apollo space launches admires his ambition to take us to Mars. But what I admire most is his willingness to put that ambition at risk by spending $44 billion to buy Twitter (now X) in order to defend free speech. Too often entrepreneurs will put their dream above everything else. Musk put free speech above his dream.

And it’s not just the $44 billion. Many of his actual and potential Tesla customers are left-wing environmentalists who criticize his purchase of Twitter, and later his leading D.O.G.E. If that dislike leads to lower sales and profits at Tesla, then Musk will have even fewer funds to take us to Mars.

But the outcome is not certain. Maybe a society with free speech is one that is more likely to allow Musk the freedom to take trial-and-error risks to get us to Mars. And there is a small chance that Tesla will sell more cars because of his principled stand.

Tesla owners who supported Harris for President are buying bumper stickers to slap on their Teslas that read “I Bought This Before We Knew Elon Was Crazy” (Peyser 2024, p. D4).

But consider Berkeley Professor Morgan Ames who bought a Tesla in 2013. Even though she did not like Elon Musk’s views she later bought a second Tesla “because she couldn’t find other electric cars that matched Tesla’s capabilities” (Peyser 2024, p. D4).

And there is Oklahoman Sean Ziese who said to his wife: “If Elon is going to start supporting conservatives and free speech, I’m going to start supporting Elon, even though I hate E.V.s” (Ziese as quoted in Peyser 2024, p. D4). Then Ziese went out and bought himself a Tesla Cybertruck.

Ziese now concludes that his driving a Tesla Cybertruck is “a really neat experience. It never would have happened if Elon never would have bought X, and, you know, got free speech going again” (Ziese as quoted in Peyser 2024, p. D4).

The source article quoted above is:

Eve Peyser. “Tesla Owners Don’t Drive Away Quietly.” The New York Times (Thurs., December 19, 2024): D4.

(Note: the online version of the Eve Peyser article has the date Dec. 11, 2024, and has the title “For Tesla Owners, a Referendum Through Bumper Stickers.”)

Once You Experience Entrepreneurship “Everything Else Is Boring”

(p. B12) C. Richard Kramlich, an early investor in Silicon Valley who co-founded the investment giant New Enterprise Associates, helping to fuel the booming tech industry, died on Saturday [Feb. 1, 2025] at his home in Oakville, Calif., in the Napa Valley. He was 89.

. . .

He co-founded his own firm, New Enterprise Associates, or NEA, building it from an initial $16 million fund in the 1970s to one that now oversees investments of nearly $26 billion.

But he stood out among Silicon Valley’s sea of swashbuckling financiers because of his grace and kindness, said Scott Sandell, the chief investment officer and executive chairman of NEA.

. . .

When he was 13, Dick followed in his father’s entrepreneurial footsteps, starting his own “little lightbulb company,” he said in a 2015 interview with the Computer History Museum. “My father encouraged me to do it if I used my own money, and so I bought half a train car worth of lightbulbs from Sylvania Corporation” and resold them from his bedroom.

He added: “I come from three generations of entrepreneurs, and once you get it in your DNA, everything else is boring.”

. . .

. . . Mr. Kramlich met a pair of entrepreneurs who were both named Steve (Jobs and Wozniak). Their company, Apple Computer, was not as good as two other personal computer companies in the market, Mr. Kramlich said in 2015. But their sense of design and entrepreneurial spark were impressive. “They had pizazz,” he said, “where the other two companies were more engineering oriented.”

. . .

Venture capital investing is designed to absorb many losses in pursuit of one home-run deal, leaving a graveyard of failed start-ups along the way. But Mr. Kramlich was known for sticking with struggling investments long after others had abandoned them.

“He used to say, ‘Never say die,’” Mr. Sandell said.

In the early 1980s, Forethought, the start-up behind PowerPoint software, was about to run out of money, and NEA’s partners refused to pony up more. So Mr. Kramlich convinced his wife that they should pause work on the house they were building on Stinson Beach and use the cash to keep the company alive instead. The gamble paid off: In 1987, Microsoft bought Forethought for $14 million, and PowerPoint went on to become one of the world’s best-known software programs.

For the full obituary see:

Erin Griffith. “Richard Kramlich, 89, A Silicon Valley Investor Revered for Humaneness.” The New York Times (Wednesday, February 8, 2025): B12.

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

(Note: the online version of the obituary has the date Feb. 6, 2025, and has the title “C. Richard Kramlich, Early Investor in Silicon Valley, Dies at 89.”)

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?”)

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.