Category: Entrepreneurship

Idaho Cut or Simplified 95% of Regulations by a “Sunset” Review

In my Openness book, I argue that government regulations bind entrepreneurs and reduce innovation. As part of an antidote, I suggest that “sunset laws,” where regulations automatically expire, if not renewed. Later, at a small conference on Adam Thierer’s latest book, I was discouraged to hear a couple of participants grant the plausibility of the “antidote,” but report that in actual practice it does not work because almost all old regulations get renewed. Some hope returned when I read a report from James Broughel of a successful sunset review process:

Idaho has proved deregulation is possible. The state repealed and revised its administrative rules code through a sunset review process in 2019. The results were dramatic. Since then, 95% of state regulations have been eliminated or simplified. The sky didn’t fall. Most regulations, when subject to genuine scrutiny, fail to justify their existence.

I will keep my eyes open on this issue, looking for more evidence.

James Broughel’s commentary is:

James Broughel. “Recipe for a Regulatory Spring Cleaning.” The Wall Street Journal (Tues., Nov. 26, 2024): A13.

(Note: the online version of the commentary has the date November 25, 2024, and has the same title as the print version.)

My book mentioned above is:

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

Adam Thierer’s book mentioned above is:

Thierer, Adam. Evasive Entrepreneurs and the Future of Governance: How Innovation Improves Economies and Governments. Washington, D.C.: Cato Institute, 2020.

Off-Label Drug Use Shows F.D.A. Phase 3 Trials Could Be Dropped, Adding New Cures and Lowering Costs

The F.D.A. allows physicians to prescribe drugs for “off-label” use. These drugs were originally approved for a different “on-label” use. For that approval the drugs had to pass through Phase 1 and Phase 2 clinical trials, mainly to show safety, and massively expensive Phase 3 clinical trials to show efficacy for the on-label use.

When off-label use is allowed, that shows that the F.D.A. is accepting drugs for a use where efficacy has NOT been shown.

This is a proof of concept for my suggestion (that I originally heard from Nobel-Prize-winner Milton Friedman) that F.D.A. regulation should be pared back to just Phase 1 and Phase 2, for safety. Since the Phase 3 trials are usually far more expensive than the Phase 1 and Phase 2 combined, this would allow far more new drugs to be developed.

If the development of new drugs was cheaper, Fajgenbaum and others would not need to spend N.I.H.’s 48 millions of taxpayer dollars to comb through already-approved drugs to see if one can be jury-rigged as a therapy for a different disease.

(p. A6) [Dr. David Fajgenbaum, an immunologist at the University of Pennsylvania and . . . Castleman patient who studies the disease] . . . has matched rare-disease patients with drugs that are already in pharmacies for other conditions for over 10 years, starting with himself.

. . .

Every Cure, a nonprofit Fajgenbaum helped found in 2022, received funding on Wednesday [Feb. 28, 2024] that could surpass $48 million from the federal Advanced Research Projects Agency for Health. Fajgenbaum and his team will spend the money to build a drug-repurposing database and algorithms that patients, doctors and researchers can use to find drugs for untreated diseases.

There are over 10,000 known rare diseases and most don’t have a drug approved to treat them. The FDA said it has approved over 19,000 prescription drugs.

The notion of finding new uses for existing drugs has been around for a long time. Once the FDA approves a drug, doctors can prescribe it off-label to patients with other conditions they think it will help. Ozempic, originally approved for people with Type 2 diabetes, is now used by millions of people without the disease for weight loss.

The National Institutes of Health and research institutions have invested over the years in drug repurposing, hoping it would be faster and less costly to find new uses for drugs that have already made it to market, a process that can take more than a decade and cost $2 billion. But systematically matching approved treatments to unmet needs has been hard.

. . .

“Our end goal is not FDA approval. Our end goal is giving patients maximum access to medications,” said Tracey Sikora, co-founder of Every Cure.

For the full story see:

Amy Dockser Marcus. “Repurposed Drugs Give People With Rare Diseases New Hope.” The Wall Street Journal (Thursday, Feb. 29, 2024 [sic]): A6.

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

(Note: the online version of the story has the date February 28, 2024 [sic], and has the title “This Doctor Found His Own Miracle Drug. Now He Wants to Do It for Others.”)

For more on Fajgenbaum’s story, read his autobiographical account:

Fajgenbaum, David. Chasing My Cure: A Doctor’s Race to Turn Hope into Action; a Memoir. New York: Ballantine Books, 2019.

F.D.A.’s Project Optimus Adds to Complexity and Length of Mandated Clinical Trials, Further Burdening Innovative Startups

One of Joseph Schumpeter’s profound subtle points in the key chapter 7 of Capitalism, Socialism and Democracy is that the kind of thinking and rules that aim for optimization, restrict the kind of creative, inspired thinking or improvisational pivoting that results in the greatest and fastest progress and flourishing. (My interpretation of Schumpeter.)

Great leaps forward have tended to originate from small startups. But increasing the size, length, and costs of mandated clinical trials, as the F.D.A. is doing with “Project Optimus,” will make it harder for small startups to survive, let alone flourish.

(p. B2) For years, Food and Drug Administration officials have expressed concern that cancer drug doses are often too high, leading to unnecessary side effects. An FDA program launched in 2021, Project Optimus, requires companies to re-examine how they set doses of cancer treatments.

This typically involves larger clinical trials to test doses to find those that optimally balance safety and efficacy. Entrepreneurs support the aim, but some fear the initiative will add time and cost to drug development, putting startups at a further disadvantage to larger competitors.

“I don’t think anybody disagrees with the idea that we’re trying to find the best thing for the patient,” said David Bearss, chief executive of biotechnology startup Halia Therapeutics. “I hope it doesn’t have unintended consequences of actually suppressing innovation.”

. . .

Because Project Optimus is still relatively new it will take a while for its full impact to be known. But it will likely add six to 12 months to the drug-development process, said Tara Raghavan, a pharmaceutical patent lawyer and partner with law firm Benesch Friedlander Coplan & Aronoff.

For the full story, see:

Brian Gormley. “FDA Drug Initiative Vexes Startups.” The Wall Street Journal (Friday, Aug 30, 2024): B2.

(Note: ellipsis added.)

(Note: the online version of the story has the date August 29, 2024, and has the title “FDA Wants Safer Cancer Drugs, but Some Startups Fear Unintended Consequences.”)

In my comments I mention Schumpeter’s chapter 7 on creative destruction that can be found in his messy, inspired masterpiece:

Schumpeter, Joseph A. Capitalism, Socialism and Democracy. 3rd ed. New York: Harper and Row, 1950.

Harold Ridley’s Innovative Project Was to Replace a Cataract with a Plexiglass Lens

I am currently working on a book on medical entrepreneurship. Harold Ridley deserves inclusion.

Innovative entrepreneurs often observe anomalies and realize how the anomalies can be put to good use, where others would not notice the anomalies, or would notice them, shrug, and forget. (In Ridley’s case the anomalie was that the plastic fragments in Cleaver’s eyes “weren’t causing any inflammation or infection.”)

Pasteur famously said that ‘chance favors a prepared mind.’ If he had read Kirzner, he might have added ‘chance also favors an alert mind.’ (Kirzner’s account of entrepreneurship emphasizes the importance of entrepreneurial alertness.)

(p. A17) On Aug. 15, 1940, Royal Air Force pilot Gordon Cleaver scrambled into the cockpit of his Hawker Hurricane and lifted into the sky.  . . .  He was shot down over Winchester. Enemy bullets shattered his canopy, showering debris into his eyes. Flying blind and in excruciating pain, Cleaver managed to escape his doomed plane and parachute to the ground.

. . .

Cleaver’s damaged eyes were examined by a 34-year-old ophthalmologist, Harold Ridley. Shards of Plexiglas from his shattered canopy remained in the pilot’s eyes. This was a disaster. Foreign bodies in the eye such as lead or shrapnel usually caused inflammation or infection so severe that the eyes often had to be removed. But Ridley noticed something peculiar: The fragments of clear plastic weren’t causing any inflammation or infection. They sat quietly inside Cleaver’s eyes, glistening in the light of the ophthalmoscope. This was a shocking discovery.

Ridley examined Cleaver multiple times. The pilot’s sight was severely damaged, but the Plexiglas remained inert in his eyes, causing no inflammation. In 1948, while Ridley was removing a cataract—a clouding of the eye’s lens—for another patient, the memory of Cleaver’s case sparked an epiphany. A medical student observing the operation said, “It’s a pity you can’t replace the cataract with a clear lens.” Ridley recalled the well-tolerated Plexiglas in Cleaver’s eyes and realized that he could use the material to make an intraocular lens that the body wouldn’t reject.

. . .

His invention has saved the sight of millions. But instead of stirring professional acclaim, Ridley’s invention was a disaster for his career. The ophthalmology establishment labeled him a heretic.

Leaders in the field accused him of malpractice, ridiculed him at science conferences and poisoned colleagues against his ideas. They argued that the procedure was a “time bomb” and that “manufacturers should be prosecuted for supplying implants.” Ridley worked for decades to improve his operation and gain converts, but fell into a deep depression. When he retired in 1971, he considered his career a failure.

For the full commentary see:

Andrew Lam. “The Doctor and the Pilot Who Saved the Eyesight of Million.” The Wall Street Journal (Monday, Feb. 8, 2025): A17.

(Note: ellipses added.)

(Note: the online version of the commentary has the date February 7, 2025, and has the same title as the print version.)

Lam’s commentary is related to his book:

Lam, Andrew. Saving Sight. Bokeelia, FL: Irie Books, 2013.

For Kirzner on entrepreneurial alertness see:

Kirzner, Israel M. Competition and Entrepreneurship. Chicago: University of Chicago Press, 1973.

Trial-and-Error Exploration of Venoms Can Yield Useful Drugs

Several decades ago the fastest path to medical advance was claimed to be theoretical science. That approach has not paid off as richly as predicted.
But it may still. (When Pets.com failed, some said we should have known you cannot make money selling pet supplies online. But now Chewy.com succeeds.) Nonetheless the contempt the theoreticians heaped upon empirical trial-and-error research was not justified. Much is still left to be learned by that method, as exemplified in the passages quoted below.

(p. D1) Efforts to tease apart the vast swarm of proteins in venom — a field called venomics — have burgeoned in recent years, and the growing catalog of compounds has led to a number of drug discoveries. As the components of these natural toxins continue to be assayed by evolving technologies, the number of promising molecules is also growing.

“A century ago we thought venom had three or four components, and now we know just one type of venom can have thousands,” said Leslie V. Boyer, a professor emeritus of pathology at the University of Arizona. “Things are accelerating because a small number of very good laboratories have been pumping out information that everyone else can now use to make discoveries.”

She added, “There’s a pharmacopoeia out there waiting to be explored.”

. . .

(p. D8) The techniques used to process venom compounds have become so powerful that they are creating new opportunities. “We can do assays nowadays using only a couple of micrograms of venom that 10 or 15 years ago would have required hundreds of micrograms,” or more, Dr. Fry said. “What this has done is open up all the other venomous lineages out there that produce tiny amounts of material.”

There is an enormous natural library to sort through. Hundreds of thousands of species of reptile, insect, spider, snail and jellyfish, among other creatures, have mastered the art of chemical warfare with venom. Moreover, the makeup of venom varies from animal to animal. There is a kind of toxic terroir: Venom differs in quantity, potency and proportion and types of toxin, according to habitat and diet, and even by changing temperatures due to climate change.

Venom is made of a complex mix of toxins, which are composed of proteins with unique characteristics. They are so deadly because evolution has honed their effectiveness for so long — some 54 million years for snakes and 600 million for jellyfish.

. . .

Numerous venom-derived drugs are on the market. Captopril, the first, was created in the 1970s from the venom of a Brazilian jararaca pit viper to treat high blood pressure. It has been successful commercially. Another drug, exenatide, is derived from Gila monster venom and is prescribed for Type 2 diabetes. Draculin is an anticoagulant from vampire bat venom and is used to treat stroke and heart attack.

The venom of the Israeli deathstalker scorpion is the source of a compound in clinical trials that finds and illuminates breast and colon tumors.

Some proteins have been flagged as potential candidates for new drugs, but they have to journey through the long process of manufacture and clinical trials, which can take many years and cost millions of dollars. In March [2022], researchers at the University of Utah announced that they had discovered a fast-acting molecule in cone snails. Cone snails fire their venom into fish, which causes the victims’ glucose levels to drop so rapidly it kills them. It holds promise as a drug for diabetes. Bee venom appears to work with a wide range of pathologies and has recently been found to kill aggressive breast cancer cells.

For the full story see:

Jim Robbins. “Venoms May Cure What Ails You.” The New York Times (Tuesday, May 3, 2022 [sic]): D1 & D5.

(Note: the online version of the story was updated May 6, 2022 [sic], and has the title “Deadly Venom From Spiders and Snakes May Also Cure What Ails You.”)

The published academic article on the use of cone snail venom to derive a new insulin for diabetes is:

Xiong, Xiaochun, Alan Blakely, Jin Hwan Kim, John G. Menting, Ingmar B. Schäfer, Heidi L. Schubert, Rahul Agrawal, Theresia Gutmann, Carlie Delaine, Yi Wolf Zhang, Gizem Olay Artik, Allanah Merriman, Debbie Eckert, Michael C. Lawrence, Ünal Coskun, Simon J. Fisher, Briony E. Forbes, Helena Safavi-Hemami, Christopher P. Hill, and Danny Hung-Chieh Chou. “Symmetric and Asymmetric Receptor Conformation Continuum Induced by a New Insulin.” Nature Chemical Biology 18, no. 5 (2022): 511-19.

The published academic article on the use of honeybee venom against breast cancer is:

Duffy, Ciara, Anabel Sorolla, Edina Wang, Emily Golden, Eleanor Woodward, Kathleen Davern, Diwei Ho, Elizabeth Johnstone, Kevin Pfleger, Andrew Redfern, K. Swaminathan Iyer, Boris Baer, and Pilar Blancafort. “Honeybee Venom and Melittin Suppress Growth Factor Receptor Activation in Her2-Enriched and Triple-Negative Breast Cancer.” npj Precision Oncology 4, no. 1 (2020): 24.

A recent book persuasively argued for the medical promise of drugs derived from “poison”:

Whiteman, Noah. Most Delicious Poison: The Story of Nature’s Toxins―from Spices to Vices. New York: Little, Brown Spark, 2023.

For the Last 30 Years, a Cure for Type 1 Diabetes “Is Just Five Years Away”

The article quoted below describes the “despair” of many with chronic diseases, and there willingness to “become human guinea pigs,” taking new therapies that may have risks, but also have some unknown change of a cure.

We should allow adults to make this choice. First because we respect their right to freedom. Second because we do not want to take away their hope, which is a key component of well-being. Third because allowing volunteers to try bold uncertain therapies, we will progress further and faster to cures.

Note that substantial funding for bold experiments is from a foundation headed by a doctor who himself has Type 1 diabetes. He has skin in the game, a sense of urgency.

Note also that a small pharma firm made progress, and convinced sufferers of the disease that the firm sincerely was mission-oriented. But ViaCyte was also severely financially constrained, given the huge costs of Phase 3 clinical trials. They were bought by Vertex, a company that started out small with the same mission-oriented passion (see Worth 1994) but seemed to lose some of that passion as they grew, due to the need to hire those who were good at raising money and dealing with regulators (see Worth 2014). Is it meaningful that an early success of Vertex was the drug Kalydeco for the relatively rare cystic fibrosis disease and that much of their financing was from a foundation of parents of children with cystic fibrosis, parents who felt plenty of urgency.

The odds are against Vertex curing Type 1 diabetes, but I hope they beat the odds.

If we want to better the odds for a cure, we should make drug development an order of magnitude cheaper by ending the mandate for Phase 3 clinical trials (in other words, we regulate only for safety, no longer for efficacy). Then small, passionate, entrepreneurial firms like ViaCyte can survive, thrive, and bring cures to market. Otherwise the financial hurdles will cause small firms like ViaCyte to sell out to large less entrepreneurial firms like Vertex.

(p. D5) In the three decades since she was first diagnosed with Type 1 diabetes, Lisa Hepner has clung to a vague promise she often heard from doctors convinced medical science was on the cusp of making her body whole again. “Stay strong,” they would say. “A cure is just five years away.”

. . .

“‘The cure is five years away’ has become a joke in the diabetes community,” Ms. Hepner said. “If it’s so close, then what’s taking so long? And in the meantime, millions of us have died.”

. . .

Therapies developed from human embryonic stem cells, many experts say, offer the best hope for a lasting cure. “The Human Trial” offers a rare glimpse into the complexities and challenges of developing new therapies — both for the patients who volunteer for the grueling clinical trials required by the Food and Drug Administration, and for the ViaCyte executives constantly scrambling to raise the money needed to bring a new drug to market. These days, the average cost, including the many failed trials along the way, is a billion dollars.

At a time when the soaring price of insulin and other life-sustaining drugs has tarnished public perceptions of the pharmaceutical industry, the film is also noteworthy for its admiring portrayal of a biotech company whose executives and employees appear genuinely committed to helping humanity.  . . .

. . .

“The Human Trial,” which can also be viewed online, has become a rallying cry for Type 1 patients, many of whom believe only greater visibility can unleash the research dollars needed to find a cure.

Those who have seen the film have also been fortified by seeing their own struggles and dashed hopes reflected in the journeys of the film’s two main subjects, Greg Romero and Maren Badger, who became among the first patients to have the experimental cell pouches implanted under their skin.

The despair that drives them to become human guinea pigs can be hard to watch. Mr. Romero — whose father also had the disease, went blind before he was 30 and then died prematurely — confronts his own failing vision while grappling with the pain of diabetes-related nerve damage. “I hate insulin needles, I hate the smell of insulin. I just want this disease to go away,” Mr. Romero, 48, says numbly at one point in the film.

. . .

. . . there is more recent news that did not make it into the film. [In July 2022], ViaCyte was acquired by Vertex, the competing biotech company that has been developing its own stem-cell treatment. That treatment has shown early success, and last year the company announced that a retired postal worker who took part in clinical trials had been cured of Type 1 diabetes.

After almost a lifetime of hearing a cure was just around the corner, Dr. Aaron Kowalski, chief executive of the JDRF (Juvenile Diabetes Research Foundation), the world’s biggest funder of Type 1 research, counts himself as an optimist. A dozen more drug companies are pursuing a cure than a decade ago, he said, and the organization this year plans to spend $100 million on cure research. “It’s not a matter of if this will happen, it’s a matter of when,” said Dr. Kowalski, who is a scientist and has had the disease since childhood, as has a younger brother. “Our job is to make sure it happens faster.”

For the full review see:

Andrew Jacobs. “The Long, Long Wait for a Diabetes Cure.” The New York Time (Tuesday, Aug. 9, 2022 [sic]): D5.

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

(Note: the online version of the review was updated Aug. 10, 2022 [sic], and has the same title as the print version. Where the two versions have slightly different wording, the passages quoted above follow the online version.)

Werth’s account of the founding and early mission-orientation of Vertex is:

Werth, Barry. The Billion-Dollar Molecule: One Company’s Quest for the Perfect Drug. New York: Simon & Schuster, 1994.

Werth’s account the later growth and risk of loss of mission-orientation is:

Werth, Barry. The Antidote: Inside the World of New Pharma. New York: Simon & Schuster, 2014.

Using the Blood of the Young to Rejuvenate the Organs of the Old

The strange longevity therapy described in the passages quoted below, are hard to test, especially if started at a time in life early enough to do the most good.

Phase 3 clinical trials to establish the efficacy of a therapy are in general very expensive, and they are especially very expensive for therapies aimed at extending lifespan. To know the efficacy of such therapies you have to run the trial for many years, before you can learn the lifespans of all of those in the trial.

This may be one reason why pharma firms instead invest in incremental improvements in health tested for those predicted to be near the end of their lives.

Azra Raza claims that the most promising therapies for cancer would be those applied early in the disease. But it is precisely these candidate therapies that would be most expensive to test through a hyper-expensive Phase 3 clinical trial. The result? Unnecessarily slow progress in curing cancer.

(p. B3) Several years ago, scientists studying aging at the Harvard Stem Cell Institute used a somewhat Frankensteinian technique known as parabiosis — surgically joining a young mouse and an old mouse so that they share blood — to see what would happen to the heart and skeletal muscle tissue. They knew from previous research that putting young blood in old mice caused them to grow biologically younger, and that young mice exposed to old blood aged faster.

The Harvard researchers, Amy Wagers and Dr. Richard Lee, found that the old mouse’s heart tissue had been repaired and rejuvenated, becoming young again. In fact, the size of the old mouse’s heart had reduced to that of a young heart.

“We all wondered, what’s the magic stuff in the blood?” said Lee Rubin, a professor of stem cell and regenerative medicine at Harvard and the co-director of the neuroscience program at the Stem Cell Institute. The “magic” they identified was a protein, GDF11, one of tens of thousands produced in the human body.  . . .  The scientists’ discoveries were published in the journals Cell and Science in 2013 and 2014.

. . .

“We’re interested in proteins like GDF11 that are excreted into the bloodstream because those can cause changes throughout the body,” said Dr. Mark Allen, the chief executive of Elevian. “And those are the kind of changes we want.”

. . .

The initial research into the rejuvenating properties of GDF11 has gotten some pushback from the scientific community. In 2015, after Dr. Wagers and Dr. Lee had published their results, a group of researchers led by David Glass, the executive director of the Novartis Institutes for Biomedical Research in Cambridge, Mass., at the time, challenged the accuracy of their findings in an article in the journal Cell Metabolism. The Harvard researchers subsequently countered the Novartis team’s findings in another paper published later that year in the journal Circulation Research, in which the Harvard researchers cited a problem with the Novartis team’s findings.

Dr. Glass, who is now at the biotechnology company Regeneron, said in a recent email that he stands by his original work, which showed that GDF11 inhibits, rather than helps, muscle regeneration. But, he added, “our work still leaves open the possibility that there could be positive effects of GDF11 in particular settings.”

Dr. Allen said that since the original controversy, Elevian’s research team has reproduced and extended its original findings in multiple studies, but none have yet been published in peer-reviewed journals. However, institutions unrelated to Elevian have conducted and published many preclinical studies demonstrating the therapeutic efficacy of rGDF11 (the form of GDF11 developed in a lab) in treating age-related diseases.

. . .

A significant challenge lies ahead for all of these companies: Commercializing a drug for aging is nearly impossible because the F.D.A. doesn’t recognize aging as a disease to be treated. And even if it were considered a disease, the clinical studies required to prove that a treatment for it worked would take many years.

“It is likely that clinical studies to see if some drug slows aging — and thereby delays the many consequences of aging — would take a long time,” Dr. Miller said.

. . .

The next big hurdle for Elevian is scaling its manufacturing, which requires specialized equipment and conditions. So much research is being conducted in biotech that contract manufacturers are “full up,” Dr. Allen said. “They are busy with Covid-related work, and there has been a lot of funding in biotech generally,” he added. “So it’s a challenge finding the space that meets our specifications.”

. . .

“By targeting fundamental mechanisms of aging, we have the opportunity to treat or prevent multiple aging-related diseases and extend the health span,” he said. “We want to make 100 the new 50.”

For the full story see:

Eilene Zimmerman. “Biotech Start-Up Invests in Anti-Aging Therapy.” The New York Times (Monday, August 1, 2022 [sic]): B3.

(Note: the online version of the story has the date July 19, 2022 [sic], and has the title “Can a ‘Magic’ Protein Slow the Aging Process?”)

The published academic articles supporting the promising effects of GDF11 are:

Katsimpardi, Lida, Nadia K. Litterman, Pamela A. Schein, Christine M. Miller, Francesco S. Loffredo, Gregory R. Wojtkiewicz, John W. Chen, Richard T. Lee, Amy J. Wagers, and Lee L. Rubin. “Vascular and Neurogenic Rejuvenation of the Aging Mouse Brain by Young Systemic Factors.” Science 344, no. 6184 (May 9, 2014): 630-34.

Loffredo, Francesco S., Matthew L. Steinhauser, Steven M. Jay, Joseph Gannon, James R. Pancoast, Pratyusha Yalamanchi, Manisha Sinha, Claudia Dall’Osso, Danika Khong, Jennifer L. Shadrach, Christine M. Miller, Britta S. Singer, Alex Stewart, Nikolaos Psychogios, Robert E. Gerszten, Adam J. Hartigan, Mi-Jeong Kim, Thomas Serwold, Amy J. Wagers, and Richard T. Lee. “Growth Differentiation Factor 11 Is a Circulating Factor That Reverses Age-Related Cardiac Hypertrophy.” Cell 153, no. 4 (May 9, 2013): 828-39.

Poggioli, Tommaso, Ana Vujic, Peiguo Yang, Claudio Macias-Trevino, Aysu Uygur, Francesco S. Loffredo, James R. Pancoast, Miook Cho, Jill Goldstein, Rachel M. Tandias, Emilia Gonzalez, Ryan G. Walker, Thomas B. Thompson, Amy J. Wagers, Yick W. Fong, and Richard T. Lee. “Circulating Growth Differentiation Factor 11/8 Levels Decline with Age.” Circulation Research 118, no. 1 (Jan. 2016): 29-37.

Sinha, Manisha, Young C. Jang, Juhyun Oh, Danika Khong, Elizabeth Y. Wu, Rohan Manohar, Christine Miller, Samuel G. Regalado, Francesco S. Loffredo, James R. Pancoast, Michael F. Hirshman, Jessica Lebowitz, Jennifer L. Shadrach, Massimiliano Cerletti, Mi-Jeong Kim, Thomas Serwold, Laurie J. Goodyear, Bernard Rosner, Richard T. Lee, and Amy J. Wagers. “Restoring Systemic Gdf11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle.” Science 344, no. 6184 (May 9, 2014): 649-52.

The book by Asra Raza that I praise in my introductory comments is:

Raza, Azra. The First Cell: And the Human Costs of Pursuing Cancer to the Last. New York: Basic Books, 2019.

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.”)

Regulators Do Not Understand the Sense of Urgency of Some Who Are Dying

Many know that the first gift of Prometheus to humanity was fire. Fewer know that his second gift was blind hope. International value surveyor Ronald Inglehart concluded that happiness depends less on current status than on hope for the future.

Many who are facing death without any standard therapy to save them, are anxious to try a Hail Mary experiment–a potential therapy with many risks, but with a possible path forward, with hope.

A libertarian or classical liberal says that they have the right to choose hope.

In the concluding passages quoted below it is easy to sense the hope that the pig kidney transplant gave Tawana Looney.

(p. A18) A 53-year-old Alabama woman with kidney failure who waited eight years for an organ transplant has received a kidney harvested from a genetically modified pig, NYU Langone Health surgeons announced on Tuesday [Dec. 17, 2024].

The patient, Towana Looney, went into surgery just before Thanksgiving. She was in better health than others who have received porcine organs to date and left the hospital 11 days after the procedure.

. . .

Dr. Robert Montgomery, director of the NYU Langone Transplant Institute, co-led the surgery with Dr. Jayme Locke, a transplant surgeon who applied two years ago for approval from the Food and Drug Administration to perform the operation for Ms. Looney.

. . .

The experimental procedure was approved by the Food and Drug Administration under its expanded access or compassionate use program, which allows unapproved products to be used when patients have life threatening conditions.

. . .

About two years ago, Dr. Locke contacted Ms. Looney. Dr. Locke was intent on finding better solutions for patients with kidney failure, which is rampant in Alabama and disproportionately affects the state’s Black residents.

It was the beginning of a conversation that spanned nearly two years while the physician sought special F.D.A. permission to do the xenotransplant on Ms. Looney, who was eager to get started.

“I said, ‘OK, where do I sign?’” Ms. Looney recalled.

“But she said, ‘This is new territory. This is new ground. I don’t know what might happen, and a lot of things could go wrong here.’ I said, ‘OK, when are we going to do it?’ And she went through all the if’s and and’s and what might happen again.”

The dialogue continued on and off for months. “We talked every day, and every day we talked she said, ‘Are you sure?’ And I said, ‘I’m positive. My mind is made up,’” Ms. Looney said.

Last month, while Ms. Looney was sitting in her dialysis chair during her morning treatment, her phone rang. It was Dr. Locke, who asked, “How do you feel about flying up to New York?”

Dr. Locke explained that she would do the surgery with Dr. Montgomery, the mentor who trained her.

“I said, ‘But what about Christmas? What about Thanksgiving?’ ” Ms. Looney said.

“She said, ‘It is going to be the best Christmas present you ever got.’ I said, ‘Yes, ma’am, it is.’”

For the full story see:

Roni Caryn Rabin. “Alabama Woman Gets Nation’s 3rd Pig Kidney Transplant.” The New York Times (Wednesday, December 18, 2024): A18.

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

(Note: the online version of the story has the date Dec. 17, 2024, and has the title “Alabama Woman Receives Nation’s Third Pig Kidney Transplant.”)

Chinese Communist Regulators Will Want to Deep-Six DeepSeek

Many policy experts have worried than China’s economy will surpass the economy of the United States. If we lived in a world of totally free trade, I would not care if this happened. Economics is not a competitive sport where one team can win only if another team loses. A free economy is not a zero-sum game. If you are OK with me mixing metaphors: a rising tide really does lift all boats. (Amar Bhidé (quoting Paul Krugman, if memory serves) does a good job of making this point in The Venturesome Economy.)

But even though it wouldn’t bother me, China’s economy will not surpass that of the United States if China continues to oppressively regulate its economy and we continue to exuberantly unregulate our economy. An economy thrives when entrepreneurs thrive and entrepreneurs thrive when unregulated.

Consider the recent hand-wringing over the recently announced DeepSeek Chinese A.I. program. The Chinese Communists will be especially energetic in regulating entrepreneurs in the A.I. sector because the Communists cannot afford to have Chinese A.I. programs giving true answers to questions in any way related to the Chinese economy, or to the corruption and authoritarianism of the Chinese Communist regime. A.I. policy expert Barath Harithas understates the situation when he says: “Overregulation and the need to adhere to ‘core socialist values’ could risk neutering A.I.’s potential” (as quoted in Pierson and Wang 2025, p. A4).

Barath Haritas’s statement on overregulation of A.I. in China can be found in:

David Pierson and Berry Wang. “Success of DeepSeek Lifts China, but Party May Halt Its Progress.” The New York Times (Tues., February 4, 2025): A4.

(Note: the online version of the article has the date February 2, 2025, and has the title “DeepSeek Is a Win for China in the A.I. Race. Will the Party Stifle It?”)

The book by Amar Bhidé that I praise in my initial comments is:

Bhidé, Amar. The Venturesome Economy: How Innovation Sustains Prosperity in a More Connected World. Princeton, NJ: Princeton University Press, 2008.

Dow Chemical CEO Oreffice Candidly Called Environmentalists “Professional Merchants of Doom”

I have the impression that few C.E.O.s today display the open candor that Ralph Nader admired in Paul Oreffice. Is that because cancel culture has been efficient at weeding out any rising executives who might be tempted to be candid? Or do I have a mistaken impression due to the press not reporting as often on the candid comments still being made by some C.E.O.s?

[I was happy to see that Oreffice had learned public speaking in a Toastmasters Club. I heard a lot about Toastmasters as a child–my father was very active in Toastmasters and was eventually elected President of the whole international self-help organization.]

(p. C6) In a 1977 speech at Central Michigan University, Jane Fonda accused Dow Chemical of exposing workers to dangerous substances and not paying its fair share of taxes. Paul Oreffice, who was then president of Dow’s U.S. operations, sent a letter to the university denouncing Fonda as “an avowed communist sympathizer” who was spreading “venom against free enterprise.”

He also cut off Dow’s donations to the university.

. . .

Addressing a business conference in 1979, Oreffice described environmentalists as “professional merchants of doom” and enemies who were destroying free enterprise, according to a Washington Post report.

. . .

Ralph Nader, the consumer-protection crusader, often was at odds with Oreffice but saw merit in his candor. “He is comparatively open to interviews, to questions from audiences, to debates,” Nader wrote in “The Big Boys,” a 1986 book written with William Taylor. “Despite his position as chief executive of a major corporation embroiled in ongoing controversies, he chooses not to hide behind company spokesmen and other bureaucratic shields.”

. . .

Oreffice resisted organization charts because he believed they “put people in boxes.”

. . .

. . ., Oreffice . . . learned public speaking at a Toastmasters club, . . .

As a CEO, he reduced costs and bureaucracy through attrition rather than mass layoffs. “How can you expect allegiance from your employees when you don’t show them any yourself?” he wrote in his memoir.

For the full obituary see:

James R. Hagerty. “An Outspoken Former CEO Of Dow Chemical.” The Wall Street Journal (Saturday, February 1, 2025): C6.

(Note: ellipses added.)

(Note: the online version of the obituary has the date January 29, 2025, and has the title “Paul Oreffice, Outspoken Former CEO of Dow Chemical, Dies at 97.” Where the wording is different between the two versions, the passages quoted above follow the online version.)

Oreffice’s memoir mentioned above is:

Oreffice, Paul. Only in America: From Immigrant to CEO. Macon, GA: Stroud & Hall Publishers, 2006.