Fraudulently Doctored Images and “Suspect Data” in Many Leading Cancer Research Papers

Charles Piller in his Doctored paints a damning picture of doctored images and suspect data rampant in the leading scientific literature on Alzheimer’s disease. Not only were leading scientists guilty of fraud, but the key institutions of scientific research (journals, universities, and government grant-making agencies) failing their oversight duty, and when outsiders stepped in to provide oversight, delayed and minimized their responses. Practicing and turning a blind eye to fraud matters, since Alzheimer’s patients are depending on this research. And researchers who do not commit fraud suffer because they appear to have worse research records than those compiled by the fraudsters. So the honest get worse academic appointments and fewer grants.

After reading Doctored I was depressed, but I at least hoped that this pathology was limited to this one (albeit an important one) area of medical research. But in the article quoted below, evidence is presented that there is substantial similar doctored images and suspect data in the field of cancer research.

A side issue in the quoted article is worth highlighting. In the absence of credible oversight from the institutions tasked with oversight, oversight is being done by competent volunteers, with the aid of A.I. These volunteers do not receive compensation for their work, and in fact are probably pay a price for it, since they alienate powerful scientists and scientific institutions. But if science is a search for truth, and truth matters for cures, they are doing a service to us all, and especially to those who suffer from major diseases such as Alsheimer’s and cancer.

On the connection with the Doctored book, it is worth noting that the article quotes Dr. Matthew Schrag, who is the most important source in Doctored. The article also quoted Elisabeth Bik, who does not have an MD like Schrag but has a PhD in microbiology, and who is another important source in Doctored.

(p. A1) The stomach cancer study was shot through with suspicious data. Identical constellations of cells were said to depict separate experiments on wholly different biological lineages. Photos of tumor-stricken mice, used to show that a drug reduced cancer growth, had been featured in two previous papers describing other treatments.

Problems with the study were severe enough that its publisher, after finding that the paper violated ethics guidelines, formally withdrew it within a few months of its publication in 2021. The study was then wiped from the internet, leaving behind a barren web page that said nothing about the reasons for its removal.

As it turned out, the flawed study was part of a pattern. Since 2008, two of its authors — Dr. Sam S. Yoon, chief of a cancer surgery division at Columbia University’s medical center, and a more junior cancer biologist — have collaborated with a rotating cast of researchers on a combined 26 articles that a British scientific sleuth has publicly flagged for containing suspect data. A medical journal retracted one of them this month after inquiries from The New York Times.

Memorial Sloan Kettering Cancer Center, where Dr. Yoon worked when much of the research was done, is now investigating the studies. Columbia’s medical center declined to comment on specific allegations, saying only that it reviews “any concerns about scientific integrity brought to our attention.”

Dr. Yoon, who has said his research could lead to better cancer treatments, did not answer repeated questions. Attempts to speak to the other researcher, Changhwan Yoon, an associate research scientist at Columbia, were also unsuccessful.

The allegations were aired in recent months in online comments on a science forum and in a blog post by Sholto David, an independent molecular biologist. He has ferreted out problems in a raft of high-profile cancer research, including dozens of papers at a Harvard cancer center that were subsequently referred for retractions or corrections.

From his flat in Wales, Dr. David pores over published images of cells, tumors and mice in his spare (p. A17) time and then reports slip-ups, trying to close the gap between people’s regard for academic research and the sometimes shoddier realities of the profession.

. . .

Armed with A.I.-powered detection tools, scientists and bloggers have recently exposed a growing body of such questionable research, like the faulty papers at Harvard’s Dana-Farber Cancer Institute and studies by Stanford’s president that led to his resignation last year.

But those high-profile cases were merely the tip of the iceberg, experts said. A deeper pool of unreliable research has gone unaddressed for years, shielded in part by powerful scientific publishers driven to put out huge volumes of studies while avoiding the reputational damage of retracting them publicly.

The quiet removal of the 2021 stomach cancer study from Dr. Yoon’s lab, a copy of which was reviewed by The Times, illustrates how that system of scientific publishing has helped enable faulty research, experts said. In some cases, critical medical fields have remained seeded with erroneous studies.

“The journals do the bare minimum,” said Elisabeth Bik, a microbiologist and image expert who described Dr. Yoon’s papers as showing a worrisome pattern of copied or doctored data. “There’s no oversight.”

. . .

Dr. Yoon, a stomach cancer specialist and a proponent of robotic surgery, kept climbing the academic ranks, bringing his junior researcher along with him. In September 2021, around the time the study was published, he joined Columbia, which celebrated his prolific research output in a news release. His work was financed in part by half a million dollars in federal research money that year, adding to a career haul of nearly $5 million in federal funds.

. . .

The researchers’ suspicious publications stretch back 16 years. Over time, relatively minor image copies in papers by Dr. Yoon gave way to more serious discrepancies in studies he collaborated on with Changhwan Yoon, Dr. David said. The pair, who are not related, began publishing articles together around 2013.

But neither their employers nor their publishers seemed to start investigating their work until this past fall, when Dr. David published his initial findings on For Better Science, a blog, and notified Memorial Sloan Kettering, Columbia and the journals. Memorial Sloan Kettering said it began its investigation then.

. . .

A proliferation of medical journals, they said, has helped fuel demand for ever more research articles. But those same journals, many of them operated by multibillion-dollar publishing companies, often respond slowly or do nothing at all once one of those articles is shown to contain copied data. Journals retract papers at a fraction of the rate at which they publish ones with problems.

. . .

“There are examples in this set that raise pretty serious red flags for the possibility of misconduct,” said Dr. Matthew Schrag, a Vanderbilt University neurologist who commented as part of his outside work on research integrity.

. . .

Experts said the handling of the article was symptomatic of a tendency on the part of scientific publishers to obscure reports of lapses.

“This is typical, sweeping-things-under-the-rug kind of nonsense,” said Dr. Ivan Oransky, co-founder of Retraction Watch, which keeps a database of 47,000-plus retracted papers. “This is not good for the scientific record, to put it mildly.”

For the full story, see:

Benjamin Mueller. “Cancer Doctor Is in Spotlight Over Bad Data.” The New York Times. (Fri., February 16, 2024): A1 & A17.

(Note: ellipses added.)

(Note: the online version has the date Feb. 15, 2024 [sic], and has the title “A Columbia Surgeon’s Study Was Pulled. He Kept Publishing Flawed Data.”)

Piller’s book mentioned in my initial comments is:

Piller, Charles. Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s. New York: Atria/One Signal Publishers, 2025.

“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.

Ramaswamy Avowed That the F.D.A. “Erects Unnecessary Barriers to Innovation”

The New York Times article quoted below worried that if Vivek Ramaswamy succeeded in “slashing regulation” of drugs, his own drug development firm would have benefitted. Maybe so, but that misses the main point–all the rest of us also would have benefitted by medical entrepreneurs being allowed to create more and quicker cures. Presumably The New York Times was relieved when Ramaswamy resigned from DOGE, but I was discouraged.

I was in favor of Elon Musk’s push to reduce the number of federal employees. But I was even more in favor of Vivek Ramaswamy’s push to deregulate innovative entrepreneurs.

[By the way, isn’t it predictable that The New York Times delights in highlighting Roivant’s one failure, but gives only passing scant mention to its six successes?]

(p. A10) Vivek Ramaswamy is the less famous and less wealthy half of the duo of billionaires that President-elect Donald J. Trump has designated to slash government costs.

. . .

At 39, he is one of the world’s youngest billionaires, having made his fortune in the pharmaceutical industry.  . . .

Mr. Ramaswamy, who owns a stake currently valued at nearly $600 million in a biotechnology company he started, has called for changes at the Food and Drug Administration that would speed up drug approvals.

. . .

Since being named to jointly lead DOGE, Mr. Ramaswamy had until recently been posting on Mr. Musk’s social media site X, hinting about where he may look to make changes in the government.

He called for slashing regulation, not just cutting government spending. He pointed to federal workers focused on diversity as potential targets for “mass firings.”

And he has been taking aim at the F.D.A. “My #1 issue with FDA is that it erects unnecessary barriers to innovation,” he wrote on X. He criticized the agency’s general requirement that drugmakers conduct two successful major studies to win approval rather than one.

Mr. Ramaswamy founded his biotechnology company, Roivant Sciences, in 2014, betting that he could find hidden gems whose potential had been overlooked by large drugmakers. The idea was to hunt for experimental medications languishing within large pharmaceutical companies, buy them for cheap and spin out a web of subsidiaries to bring them to market.

The venture is best known for a spectacular failure.

In 2015, Mr. Ramaswamy whipped up hype and investment around one of his finds, a potential treatment for Alzheimer’s disease being developed by one of his subsidiaries, Axovant. Two years later, a clinical trial showed that it did not work, erasing more than $1.3 billion in Axovant’s stock value in a single day.

Mr. Ramaswamy personally lost money on paper on the failure, but thanks to the savvy way he had structured his web of companies he and Roivant weathered the storm. Six products have won F.D.A. approval, and today Roivant has a market valuation of $8 billion.

Mr. Ramaswamy sold some of his Roivant stock to take a large payout in 2020, reporting nearly $175 million in capital gains on his tax return that year. But he is still one of the company’s largest shareholders.

If Mr. Ramaswamy recommends changes that speed up drug approvals through DOGE, that could be good news for Roivant, which is developing drugs that might come up for approval during Mr. Trump’s second term. The faster it can get medicines onto the market, the more valuable the company — and Mr. Ramaswamy’s stake in it — stands to become.

For the full story see:

Rebecca Robbins, Maureen Farrell and Jonathan Weisman. “From Ramaswamy’s High-Profile Perch, a Web of Potential Conflicts.” The New York Times (Thursday, January 16, 2025): A10.

(Note: ellipses added.)

(Note: the online version of the story has the date Jan. 15, 2025, and has the title “Ramaswamy Has a High-Profile Perch and a Raft of Potential Conflicts.” At one point this entry was posted on March 30. I had not noted that another entry had been posted for March 30, so for consistency I moved this entry to April 23.)

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.”)

Medical Oversight Boards Jeopardize Patient Safety by Ignoring or Forgiving the “Egregious Misconduct” of Healthcare Providers

(p. C7) In her excellent book, “The Licensing Racket,” the Vanderbilt law professor Rebecca Haw Allensworth presents plenty of cases of hair braiders, barbers and interior decorators who have been prevented from working by license restrictions that inflate prices without improving safety or quality. But Ms. Allensworth has bigger targets in mind.

Most people will concede that licensing for hair braiders and interior decorators is excessive while licensing for doctors, nurses and lawyers is essential. Hair braiders pose little to no threat to public safety, but subpar doctors, nurses and lawyers can ruin lives. To Ms. Allensworth’s credit, she asks for evidence. Does occupational licensing protect consumers? The author focuses on the professional board, the forgotten institution of occupational licensing.

. . .

(p. C8) You might hope that boards that oversee nurses and doctors would prioritize patient safety, but Ms. Allensworth’s findings show otherwise. She documents a disturbing pattern of boards that have ignored or forgiven egregious misconduct, including nurses and physicians extorting sex for prescriptions, running pill mills, assaulting patients under anesthesia and operating while intoxicated.

In one horrifying case, a surgeon breaks the white-coat code and reports a fellow doctor for performing a surgery so catastrophically botched that he assumes the practitioner must be an imposter. Others also report “Dr. Death” to the board. But Ms. Allensworth notes, “at the time of the complaints to the medical board, [Dr. Death] was only one third of the way through the thirty-seven spinal surgeries he would perform, thirty-three of which left the patients maimed or dead.” The board system seems incapable of acting decisively and Dr. Death’s rampage is only ended definitively when he is indicted—the initial charges include “assault with a deadly weapon,” the scalpel—and eventually imprisoned.

No system is perfect, but Ms. Allensworth’s point is that the board system is not designed to protect patients or consumers. She has a lot of circumstantial evidence that signals the same conclusion. The National Practitioner Data Bank (NPDB), for example, collects data on physician misconduct and potential misconduct as evidenced by medical-malpractice lawsuits. But “when Congress tried to open the database to the public, the [American Medical Association] ‘crushed it like a bug.’”

One of the most infuriating aspects of the system is that the AMA and the boards limit the number of physicians with occupational licensing, artificially scarce residency slots and barriers preventing foreign physicians from practicing in the U.S. Yet when a physician is brought before a board for egregious misconduct, the AMA cites physician shortage as a reason for leniency. When it comes to disciplining bad actors, the mantra seems to be that “any physician is better than no physician,” but when it comes to allowing foreign-trained doctors to practice in the U.S., the claim suddenly becomes something like “patient safety requires American training.”

. . .

I agree that licensing boards have failed to effectively discipline their members, but I think we should eliminate restrictions on supply. The adage “any physician is better than no physician” should not be a shield for negligent doctors, but it underscores an essential truth. The real harm lies in the scarcity created by licensing.

. . .

Voluntary certification can effectively replace many occupational licenses. Consider computer security, one of the most critical fields for consumer safety. Instead of requiring occupational licenses, professionals in this field rely on certifications such as the CISSP (Certified Information Systems Security Professional) to demonstrate expertise and competence.

. . .

The medical profession is unlikely to be delicensed, but as Ms. Allensworth’s book shows, we shouldn’t let the AMA dictate the terms of medical education. Many European countries offer combined undergraduate and medical degree programs that take only six years, compared to the eight or more years required in the U.S.

Advances in artificial intelligence, which Ms. Allensworth doesn’t explore, may also catalyze reform. AI is already transforming fields such as legal research and medical diagnostics, automating tasks once reserved for licensed professionals. As these technologies advance, they can reduce reliance on rigid licensing systems by ensuring quality and safety through innovative tools.

For the full review see:

Alex Tabarrok. “Permission To Join The Field.” The Wall Street Journal (Saturday, Feb. 8, 2025): C7-C8.

(Note: ellipses added.)

(Note: the online version of the review has the date February 7, 2025, and has the title “‘The Licensing Racket’: There’s a Board for That.”)

The book under review is:

Allensworth, Rebecca Haw. The Licensing Racket: How We Decide Who Is Allowed to Work, and Why It Goes Wrong. Cambridge, MA: Harvard University Press, 2025.

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?”)

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.

Regulations Discourage Search for Magic Bullet Cures

The so-called “Inflation Reduction Act” mandates that several of the biggest blockbuster drugs must have prices negotiated between Medicare and Pharma firms. As the commentary quoted below suggests, this creates an incentive for Pharma firms to develop many middling drugs rather than a couple of blockbuster drugs. Paul Ehrlich’s “magic bullet” may be impossible, but we will never know if no-one is trying to discover it.creates an

(p. B10) A true home run in the drug industry is when a company develops a mega-blockbuster that transforms its finances for years.

But with Medicare trying to bring costs down by targeting the industry’s most expensive drugs, a portfolio of medium-size moneymakers that can keep your name off the U.S. government’s naughty list can be a wise strategy.

That is at least one reason why big pharma is investing heavily in biotech companies developing antibody-drug conjugates. Known as ADCs, these treatments work like a guided missile by pairing antibodies with toxic agents to fight cancer. In short, they enable a more targeted form of chemotherapy that goes straight into the cancer cells while minimizing harm to healthy cells.

. . .

One reason most ADCs aren’t likely to become mega-blockbusters like Keytruda, a cancer immunotherapy that has earned 35 approvals across 16 types of cancer, is that they aren’t one-size-fits-all drugs. Instead, they are designed to target a specific protein that is expressed on the surface of a cancer cell. That means that each drug is made with an antibody targeting a subset of cancer. There are more than 100 ADCs being tested in humans by pharma and biotech companies.

For the full commentary see:

David Wainer. “Heard on the Street; Drug Industry’s Secret Weapon: ‘Guided Missiles’.” The Wall Street Journal (Friday, Oct. 27, 2023 [sic]): B10.

(Note: ellipsis added.)

(Note: the online version of the commentary has the date October 26, 2023 [sic], and has the title “Heard on the Street; ‘Guided Missile Drugs’ Could Be Big Pharma’s Secret Weapon.”)

Time Constraints for Tenure, Promotion, and Funding Decisions Lead Academic Biologists to Over-Study Already-Studied Genes

George Stigler argued that when most economists were self-funded business practitioners economics was more applied and empirical, while after most economists were academics funded by endowments or the government economics became less applied and more formal. [In a quick search I failed to identify the article where Stigler says this–sorry.] A similar point was made to science more broadly by Terence Kealey in his thought-provoking The Economic Laws of Scientific Research. The article quoted below argues persuasively that research on human genes is aligned with the career survival goals of academics, rather than with either the faster advance of science or the quicker cure of diseases like cancer. The alignment could be improved if more of research funding came from a variety of private sources.

(p. D3) In a study published Tuesday [Sept. 18, 2018] in PLOS Biology, researchers at Northwestern University reported that of our 20,000 protein-coding genes, about 5,400 have never been the subject of a single dedicated paper.

Most of our other genes have been almost as badly neglected, the subjects of minor investigation at best. A tiny fraction — 2,000 of them — have hogged most of the attention, the focus of 90 percent of the scientific studies published in recent years.

A number of factors are largely responsible for this wild imbalance, and they say a lot about how scientists approach science.

. . .

It was possible, . . ., that scientists were rationally focusing attention only on the genes that matter most. Perhaps they only studied the genes involved in cancer and other diseases.

That was not the case, it turned out. “There are lots of genes that are important for cancer, but only a small subset of them are being studied,” said Dr. Amaral.

. . .

A long history helps, . . . . The genes that are intensively studied now tend to be the ones that were discovered long ago.

Some 16 percent of all human genes were identified by 1991. Those genes were the subjects of about half of all genetic research published in 2015.

One reason is that the longer scientists study a gene, the easier it gets, noted Thomas Stoeger, a post-doctoral researcher at Northwestern and a co-author of the new report.

“People who study these genes have a head start over scientists who have to make tools to study other genes,” he said.

That head start may make all the difference in the scramble to publish research and land a job. Graduate students who investigated the least studied genes were much less likely to become a principal investigators later in their careers, the new study found.

“All the rewards are set up for you to study what has been well-studied,” Dr. Amaral said.

“With the Human Genome Project, we thought everything was going to change,” he added. “And what our analysis shows is pretty much nothing changed.”

If these trends continue as they have for decades, the human genome will remain a terra incognito for a long time. At this rate, it would take a century or longer for scientists to publish at least one paper on every one of our 20,000 genes.

That slow pace of discovery may well stymie advances in medicine, Dr. Amaral said. “We keep looking at the same genes as targets for our drugs. We are ignoring the vast majority of the genome,” he said.

Scientists won’t change their ways without a major shift in how science gets done, he added. “I can’t believe the system can move in that direction by itself,” he said.

Dr. Stoeger argued that the scientific community should recognize that a researcher who studies the least known genes may need extra time to get results.

“People who do something new need some protection,” he said.

For the full commentary see:

Carl Zimmer. “Matter; The Problem With DNA Research.” The New York Times (Tuesday, September 25, 2018 [sic]): D3.

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

(Note: the online version of the commentary has the date Sept. 18, 2018 [sic], and has the title “Matter; Why Your DNA Is Still Uncharted Territory.” Where there are differences in wording between the versions, the passages quoted above follow the online version.)

The paper in PLOS Biology co-authored by Thomas Stoeger and mentioned above is:

Stoeger, Thomas, Martin Gerlach, Richard I. Morimoto, and Luís A. Nunes Amaral. “Large-Scale Investigation of the Reasons Why Potentially Important Genes Are Ignored.” PLOS Biology 16, no. 9 (2018): e2006643.

Kealey’s book, praised above, is:

Kealey, Terence. The Economic Laws of Scientific Research. New York: St. Martin’s Press, 1996.

“Most Published Research Findings Are False”

(p. C1) How much of biomedical research is actually wrong? John Ioannidis, an epidemiologist and health-policy researcher at Stanford, was among the first to sound the alarm with a 2005 article in the journal PLOS Medicine. He showed that small sample sizes and bias in study design were chronic problems in the field and served to grossly overestimate positive results. His dramatic bottom line was that “most published research findings are false.”

The problem is especially acute in laboratory studies with animals, in which scientists often use just a few animals and fail to select them randomly. Such errors inevitably introduce bias. Large-scale human studies, of the sort used in drug testing, are less likely to be compromised in this way, but they have their own failings: It’s tempting for scientists (like everyone else) (p. C2) to see what they want to see in their findings, and data may be cherry-picked or massaged to arrive at a desired conclusion.

A paper published in February [2017] in the journal PLOS One by Estelle Dumas-Mallet and colleagues at the University of Bordeaux tracked 156 biomedical studies that had been the subject of stories in major English-language newspapers. Follow-up studies, they showed, overturned half of those initial positive results (though such disconfirmation rarely got follow-up news coverage). The studies dealt with a wide range of issues, including the biology of attention-deficit hyperactivity disorder, new breast-cancer susceptibility genes, a reported link between pesticide exposure and Parkinson’s disease, and the role of a virus in autism.

Reviews by pharmaceutical companies have delivered equally grim numbers. In 2011, scientists at Bayer published a paper in the journal Nature Reviews Drug Discovery showing that they could replicate only 25% of the findings of various studies. The following year, C. Glenn Begley, the head of cancer research at Amgen, reported in the journal Nature that he and his colleagues could reproduce only six of 53 seemingly promising studies, even after enlisting help from some of the original scientists.

With millions of dollars on the line, industry scientists overseeing clinical trials with human subjects have a stronger incentive to follow high standards. Such studies are often designed in cooperation with the U.S. Food and Drug Administration, which ultimately reviews the findings. Still, most clinical trials produce disappointing results, often because the lab studies on which they are based were themselves flawed.

For the full essay see:

Harris, Richard. “Dismal Science In the Search for Cures.” The Wall Street Journal (Saturday, April 8, 2017 [sic]): C1-C2.

(Note: bracketed year added.)

(Note: the online version of the essay was updated April 7, 2017 [sic], and has the title “The Breakdown in Biomedical Research.”)

The essay quoted above is adapted from Mr. Harris’s book:

Harris, Richard. Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions. New York: Basic Books, 2017.

The 2005 paper by Ioannidis mentioned above is:

Ioannidis, John P. A. “Why Most Published Research Findings Are False.” PLoS Medicine 2, no. 8 (2005): 696-701.