artdiamondblog.com – Page 18 – Art Diamond's web log

New Evidence American Indians Were Eating a Lot of Mammoth Meat During the Time When Mammoths Became Extinct

Scientists once thought that the extinction of megafauna like mammoths was due mainly to climate change. But the extinction in America coincided with the arrival of humans, leading some to argue that early indigenous American Indians killed off the mammoths. This goes against the politically correct stereotype that American Indians were mostly peace-loving environmentalists.

A recently published article provides additional evidence. Using a skull from the Clovis period, roughly during the period when mammoths became extinct, the authors were able to conclude from the young child’s “isotopic signature” that two-thirds of the child’s diet came from his mother’s breast-milk, and one third mainly from the meat of large mammals like mammoths. They could also infer that the mother had a diet high in mammoth meat. Summarizing the academic article in The New York Times, columnist Carl Zimmer says: “a study analyzing the ancient bones of a young child who lived in Montana suggests that early Americans hunted mammoths and other giant mammals to oblivion” (p. D3).

I am not criticizing the early American Indians. If I had been alive back then and I could obtain nutrition for me and my family by slaughtering a few mammoths, I would have tried to do so. But we are making a mistake if we reject American exceptionalism in part on the basis of a false and sanctimonious claim that the indigenous American Indians acted on morally superior environmental values.

My musings above are based partly on the commentary:

Carl Zimmer. “Mammoth: It’s What Was for Dinner.” The New York Times (Tuesday, December 10, 2024): D3.

(Note: the online version of the story has the date December 4, 2024, and has the title “Mammoth: It’s What Was Once for Dinner.”)

The academic article that is the basis for Zimmer’s commentary is:

Chatters, James C., Ben A. Potter, Stuart J. Fiedel, Juliet E. Morrow, Christopher N. Jass, and Matthew J. Wooller. “Mammoth Featured Heavily in Western Clovis Diet.” Science Advances 10, no. 49 (2024): eadr3814.

Will Cancer Die from a Magic Rifle Bullet or From Magic Shotgun Pellets?

We dream of a magic bullet that can cure all cancer. But will all “cancer” continue to be seen as one unified disease, with potentially one common cure? Or will we see many diseases, many causes, and many cures? [The idea of a “magic bullet” against a disease was born from the great Paul Ehrlich who found one of the first effective antibiotics (not to be confused with the the more recent environmentalist Paul Ehrlich who is famous for losing his bet with the great Julian Simon).]

(p. D3) A new study, published [online on] Wednesday [Oct. 2, 2019] in the journal Nature, found that fungi can make their way deep into the pancreas, which sits behind your stomach and secretes digestive enzymes into your small intestine.

. . .

One particular fungus was the most abundant in the pancreas: a genus of Basidiomycota called Malassezia, which is typically found on the skin and scalp of animals and humans, and can cause skin irritation and dandruff. . . .

The results show that Malassezia was not only abundant in mice that got pancreatic tumors, it was also present in extremely high numbers in samples from pancreatic cancer patients, said Dr. Berk Aykut, a postdoctoral researcher in Dr. Miller’s lab.

. . .

Administering an antifungal drug got rid of the fungi in mice and kept tumors from developing. And when the treated mice again received the yeast, their tumors started growing once more — an indication, Dr. Aykut said, that the fungal cells were driving the tumors’ growth.

. . .

The new study also sheds light on how fungi in the pancreas may drive the growth of tumors. The fungi activate an immune system protein called mannose-binding lectin, which then triggers a cascade of signals known to cause inflammation. When the researchers compromised the ability of the lectin protein to do its job, the cancer stopped progressing and the mice survived for longer.

For the full story see:

Knvul Sheikh. “Fungi May Have a Role In Pancreatic Cancer.” The New York Times (Tuesday, October 8, 2019 [sic]): D3.

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

(Note: the online version of the story has the date Oct. 3, 2019 [sic], and has the title “In the Pancreas, Common Fungi May Drive Cancer.” Where the wording of the versions differs, the passages quoted above follow the more detailed online version.)

The study in Nature mentioned above is:

Aykut, Berk, Smruti Pushalkar, Ruonan Chen, Qianhao Li, Raquel Abengozar, Jacqueline I. Kim, Sorin A. Shadaloey, Dongling Wu, Pamela Preiss, Narendra Verma, Yuqi Guo, Anjana Saxena, Mridula Vardhan, Brian Diskin, Wei Wang, Joshua Leinwand, Emma Kurz, Juan A. Kochen Rossi, Mautin Hundeyin, Constantinos Zambrinis, Xin Li, Deepak Saxena, and George Miller. “The Fungal Mycobiome Promotes Pancreatic Oncogenesis Via Activation of MBL.” Nature 574, no. 7777 (Oct. 10, 2019): 264-67.

Medical Mergers Can Reduce Competition and Raise Prices When Government Aids Incumbents or Fetters Entrepreneurs

The story quoted below gives useful evidence that in the recent past hospital mergers have generally resulted in higher prices. But the story is incomplete, creating the misleading impression that government antitrust action is clearly needed. My hypothesis: mergers can increase efficiency and lower patient prices, but only tend to do so when hospitals are constrained by the real or potential entry of entrepreneurial health providers. Unfortunately entry is currently very limited, often by government actions. Often new hospitals must acquire a certificate of need before they are allowed to exist.

Often, incumbent hospitals successfully object to those certificates. Federal subsidies differentially go to large incumbent hospitals. Federal Covid-relief funds went to large incumbent hospitals that used much of the funds to buy up other hospitals. Less directly, enormous government regulation creates a differential burden on the small new entrant that likely cannot afford the huge specialized staff to successfully navigate the voluminous opaque regulations.

If we want lower prices, government should allow mergers, but also stop creating constraints that discourage entry. Government should especially reduce the regulations that discourage medical entrepreneurship.

(p. D4) The nation’s hospitals have been merging at a rapid pace for a decade, forming powerful organizations that influence nearly every health care decision consumers make.

The hospitals have argued that consolidation benefits consumers with cheaper prices from coordinated services and other savings.

But an analysis conducted for The New York Times shows the opposite to be true in many cases. The mergers have essentially banished competition and raised prices for hospital admissions in most cases, according to an examination of 25 metropolitan areas with the highest rate of consolidation from 2010 through 2013, a peak period for mergers.

The analysis showed that the price of an average hospital stay soared, with prices in most areas going up between 11 percent and 54 percent in the years afterward, according to researchers from the Nicholas C. Petris Center at the University of California, Berkeley.

The new research confirms growing skepticism among consumer health groups and lawmakers about the enormous clout of the hospital groups. While most political attention has focused on increased drug prices and the Affordable Care Act, state and federal officials are beginning to look more closely at how hospital mergers are affecting spiraling health care costs.

During the Obama years, the mergers received nearly universal approval from antitrust agencies, with the Federal Trade Commission moving to block only a small fraction of deals. State officials generally looked the other way.

President Trump issued an executive order last year calling for more competition, saying his administration would focus on “limiting excessive consolidation (p. B1) throughout the health care system.” In September [2018], Congress asked the Medicare advisory board to study the trend.

. . .

Prices rise even more steeply when these large hospital systems buy doctors’ groups, according to Richard Scheffler, director of the Petris Center.

“It’s much more powerful when they already have a very large market share,” said Mr. Scheffler, who recently published a study on the issue in Health Affairs. “The impact is just enormous.”

For the full story see:

Reed Abelson. “When Hospitals Merge, Patients Often Pay More.” The New York Times (Wednesday, November 14, 2018 [sic]): B1 & B6.

(Note: ellipses added.)

(Note: the online version of the story has the same date as the print version, and has the title “When Hospitals Merge to Save Money, Patients Often Pay More.” Where the wording of the versions differs, the passages quoted above follow the online version.)

The article co-authored by Scheffler and mentioned above

Scheffler, Richard M., Daniel R. Arnold, and Christopher M. Whaley. “Consolidation Trends in California’s Health Care System: Impacts on Aca Premiums and Outpatient Visit Prices.” Health Affairs 37, no. 9 (Sept. 2018): 1409-16.

Some Medical Researchers Seek Patient Input on Execution of Studies

In the story quoted below some medical researchers are seeking patient involvement in studies, but I was disappointed to realize that the involvement is mostly superficial with the aim of getting patient agreement to be part of the study. The researchers in the story still see a big divide between patients and doctors. Doctors see patterns and create hypotheses to be tested. Patients, if they want, can stand by posters, and make minor suggestions on the execution of study design.

I suggest, more ambitiously, that patients sometimes, if allowed, can see patterns and create hypotheses. They have the incentive, the skin in the game. And sometimes they have direct experience on what works and what does not work.

(p. R6) Joel Nowak, a 66-year-old Brooklyn, N.Y., resident with metastatic prostate cancer, knows a lot about cancer research. Over the years, he has contributed blood, saliva and medical information to studies in hopes of helping investigators battle the disease.

But something has nagged at him. Almost always, Mr. Nowak says, investigators want data, “but you never hear from them again.”

Then he was asked to join a new endeavor that is trying to change that—by making participants into partners.

The Metastatic Prostate Cancer Project, launched by the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute in Boston, is trying to give participants a bigger stake in studies by asking them for input, inviting them to events and keeping them updated on progress.

. . .

Patients are . . . invited for a tour of the Broad Institute to see its gene-sequencing machines or to meet and share ideas with researchers, says Nikhil Wagle, director of the umbrella initiative.

Dr. Wagle thinks the approach has led to unusually fast and large enrollment. More than 4,000 people enrolled in the breast-cancer project and over 290 in the angiosarcoma initiative. In just a few weeks, more than 200 signed up for the prostate-cancer study.

. . .

Keeping participants up-to-date is another concern for researchers. It is an issue close to home for Corrie Painter, principal investigator of the angiosarcoma project at the Broad and one of the creators of all three of the institute’s cancer initiatives.

Dr. Painter draws on her experiences as a cancer survivor and research participant in shaping interactions with patients. She was diagnosed with angiosarcoma nearly eight years ago. Dr. Painter says that after her diagnosis, like many patients, she felt frustrated at being treated more “as passive recipients of care rather than part of the process of discovery.”

. . .

Meanwhile, some patients are taking the opportunity to play a larger role in shaping studies. Mr. Nowak, for one, joined a patient advisory council of the prostate-cancer project. Members communicate on videoconferences, email exchanges and in person. During a meeting at the Broad, researchers showed a prototype for the saliva kits that were going to be mailed to patients to collect samples.

The advocates told researchers to take “Metastatic Prostate Cancer Project” off the box. “There are a lot of men who don’t want other people to know they have cancer,” says Mr. Nowak.

For the full story see:

Amy Dockser Marcus. “Researchers Look to Enlist Patients as Partners.” The Wall Street Journal (Monday, Feb. 25, 2018 [sic]): R6.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 25, 2018 [sic], and has the title “Medical Researchers Look to Enlist Patients as Partners.” The last two ellipses above indicate where I omit sentences that appeared in the longer online version, but not in the print version.)

Marcus’s story is related to her book:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.

Large Medical Databases Would Allow Discovery and Testing of Causal Patterns of Diseases

After considerable effort, as of the writing of the article quoted below, Dr. Wagle has only been able to gather data on 375 of the roughly 155,000 metastatic breast cancer patients in the U.S. Many have long complained about the difficulty in obtaining and consolidating medical records. Exploring the reasons would take a longer article than the one quoted below. Part of the story is the Health Insurance Portability and Accountability Act of 1996 (HIPAA). It was passed to protect patient privacy, but it served as cover for medical institutions to stonewall patients, policy makers, and other medical institutions from obtaining information. The institutions make the process of obtaining medical information as slow, opaque, and onerous as possible. Partly this is a result of the general inefficiency of medical bureaucracy. Regulations limit competition among medical institutions and limit entrepreneurship, allowing inefficiencies to persist. To those who are mission-oriented within the bureaucracy, providing records may seem a lower priority than issues affecting current medical care. But also, restricting information may increase patient lock-in. Ceteris paribus, a patient may choose to stay at an institution that has long health records for the patient. Also, providing less information to third parties may make the institution less vulnerable to criticism and law suits.

Ideally, Dr. Wagle’s database would serve as a modern day version of the dusty hospital archives that Dr. William Coley pursued to find a pattern among the patients who had been spontaneously cured of their cancer in the late 1800s.

From personal experience I can say that getting patient information is easier now than it was 30 years ago, at least for the patient to obtain their own information.

An important side point is Dr. Wagle’s emphasis on the value of obtaining patient narratives, in addition to coded data. Narratives allow the discovery of additional causes or effects, beyond what the initial coders include in the coded data. Gary Klein makes this point in defending the value of what he calls “stories” (Klein 2017).

(p. D4) Dr. Nikhil Wagle thought he had a brilliant idea to advance research and patient care.

Dr. Wagle, an oncologist at the Dana Farber Cancer Institute in Boston, and his colleagues would build a huge database that linked cancer patients’ medical records, treatments and outcomes with their genetic backgrounds and the genetics of their tumors.

The database would also include patients’ own experiences. How ill did they feel with the treatments? What was their quality of life? The database would find patterns that would tell doctors what treatment was best for each patient and what patients might expect.

The holdup, he thought, would be finding patients. Instead, the real impediment turned out to be gathering their medical records.

. . .

Dr. Wagle is making data from medical records and patients’ experiences public as he gets them. After 2 1/2 years, though, he is disappointed by how little there is to share.

The patient who inspired his project had a lethal form of thyroid cancer. She was expected to die in a few months. In desperation, doctors gave her a drug that by all accounts should not have helped.

To everyone’s surprise, her tumors shrank to almost nothing, and she survived. She was an “extraordinary responder.”

Why? It turned out that her tumor had an unusual mutation that made it vulnerable to the drug.

And that got Dr. Wagle thinking. What if researchers had a database that would allow them to find these lucky patients, examine their tumors, and discover genetic mutations that predict which drugs will work?

. . .

Dr. Wagle decided to build a database, starting with metastatic breast cancer, his specialty. There are about 155,000 metastatic breast cancer patients in the United States. He would use social media, online forums and advocacy groups to reach out to patients for their records.

. . .

Startlingly, faxing “is the standard,” Ms. McGillicuddy said, for medical records requests.

The process can be frustrating. Fax numbers can be out of date. Some medical centers will not accept electronic patient signatures on the permission forms.

Sometimes, the medical centers just ignore the request — and the second request. In the end, Ms. McGillicuddy said, the project gets fewer than half the records it requests.

Then comes the laborious task of extracting medical information from the records and entering it into the database. A faxed medical record may be 100 or 200 pages long.

So far, the breast cancer project has received 450 records for 375 patients. (Each patient tends to have more than one record, because the women typically are seen at more than one medical center.)

For the full story see:

Gina Kolata. “Concealing New Cancer Treatments.” The New York Times (Tuesday, May 22, 2018 [sic]): D4.

(Note: ellipses added.)

(Note: the online version of the story has the date May 21, 2018 [sic], and has the title “New Cancer Treatments Lie Hidden Under Mountains of Paperwork.” Where the wording of the versions differs, the passages quoted above follow the online version.)

Gary Klein’s main book that I praise in my initial comments is:

Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.

When Free People Do Not Volunteer for Clinical Trials, Should Researchers Recruit Prisoners?

On the issue of how to ethically motivate prisoners to volunteer for clinical trails on the efficacy of salt-restricted diets, why not offer wages to the prisoners? Prisoners are already sometimes paid small amounts for other activities, like making license plates. Better yet, take my suggestion with a grain of salt, and settle the dispute with well-done observational studies.

(p. D3) Suppose you wanted to do a study of diet and nutrition, with thousands of participants randomly assigned to follow one meal plan or another for years as their health was monitored?

In the real world, studies like these are nearly impossible. That’s why there remain so many unanswered questions about what’s best for people to eat. And one of the biggest of those mysteries concerns salt and its relationship to health.

But now a group of eminent researchers, including the former head of the Food and Drug Administration, has suggested a way to resolve science’s so-called salt wars. They want to conduct an immense trial of salt intake with incarcerated inmates, whose diets could be tightly controlled.

The researchers, who recently proposed the idea in the journal Hypertension, say they are not only completely serious — they are optimistic it will happen.

. . .

Dr. Daniel W. Jones, a professor of medicine and physiology at the University of Mississippi School of Medicine and former president of the American Heart Association, was alarmed by the bitter arguments and increasingly personal disputes between researchers who disagree about salt.

So he invited senior medical scientists on both sides of the debate to meet in Jackson, Miss., to figure out how to settle their differences.

. . .

So suppose you do the study in prisons, said Dr. Jones. Is the research supposed to benefit the prisoners or just the population in general? If the prisoners would not benefit, the study would be unethical.

People who are not incarcerated can choose how much sodium they consume, but prisoners cannot — they eat whatever the facility provides. If there is uncertainty about the ideal amount of sodium, the experts concluded, prisoners would benefit from a study that settled the matter.

. . .

Dr. Macklin, in a telephone interview, also said many prisoners would be happy to jump in. She has taught in a maximum security facility and has studied the ethics of doing research in prisons.

“They would say they want to give back to society,” Dr. Macklin said.

. . .

Prison administrators have told Dr. Jones they would be willing to consider a proposal for a randomized trial of salt.

For the full story see:

Gina Kolata. “Looking to Prison for a Health Study.” The New York Times (Tuesday, June 5, 2018 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the story has the date June 4, 2018 [sic], and has the title “The Ideal Subjects for a Salt Study? Maybe Prisoners.”)

The academic article co-authored by Dr. Jones that proposes a randomized double-blind clinical trial (RCT) in prisons is:

Jones, Daniel W., Friedrich C. Luft, Paul K. Whelton, Michael H. Alderman, John E. Hall, Eric D. Peterson, Robert M. Califf, and David A. McCarron. “Can We End the Salt Wars with a Randomized Clinical Trial in a Controlled Environment?” Hypertension 72, no. 1 (July 2018): 10-11.

If Immortality Does Not Violate the Laws of Physics, Entrepreneurs Can Achieve It

The late Nobel-Prize-winning physicist and idiosyncratic Richard Feynman also said something similar to the quote attributed to Arram Sabeti below.

I do not believe that Feynman was explicitly named, or had any lines, in the movie “Opennheimer,” but you can see his character in the background of one scene playing the bongo drums. Perhaps he was eccentric, but I liked his views on methodology and his unpretentious, optimistic, and straightforward spirit.

(p. 9) As the longevity entrepreneur Arram Sabeti told The New Yorker: “The proposition that we can live forever is obvious. It doesn’t violate the laws of physics, so we can achieve it.”

For the full commentary see:

Dara Horn. “The Men Who Want to Live Forever.” The New York Times, SundayReview Section (Sunday, January 28, 2018 [sic]): 9.

(Note: the online version of the commentary has the date Jan. 25, 2018 [sic], and has the same title as the print version.)

The Academic “Herd Mindset” May Be the Cause of What Elon Musk Calls the “Woke Mind Virus”

(p. B3) “I listen to podcasts about the fall of civilizations to go to sleep,” Musk said this past week during an appearance at the Milken Institute conference. “So perhaps that might be part of the problem.”

One provocateur, in particular, has caught his attention of late: Gad Saad, a marketing professor at Concordia University in Montreal, and author of the book “The Parasitic Mind: How Infectious Ideas Are Killing Common Sense.”

. . .

Saad wrote that “The Parasitic Mind” was inspired, in part, by his experience in academia, where he described a herd mindset that chastised innovative thinkers. He described pushback he encountered, including his ideas being labeled as “sexist nonsense” and his efforts to use “biologically-based theorizing” to explain consumer behavior being dismissed as too reductionistic.

“The West is currently suffering from such a devastating pandemic, a collective malady that destroys people’s capacity to think rationally,” the 59-year-old Saad wrote at the beginning of his book. “Unlike other pandemics where biological pathogens are to blame, the current culprit is composed of a collection of bad ideas, spawned on university campuses, that chip away at our edifices of reason, freedom, and individual dignity.”

. . .

Another inspiration for his book, Saad writes, was his experience as a boy fleeing with other Jews from his home in Lebanon during that country’s civil war. In the book, he detailed some of the horrors he experienced, including the kidnapping of his parents.

. . .

Musk has said his concerns about Woke Mind Virus, his way of labeling progressive liberal beliefs that he says are overly politically correct and stifling to public debate and free speech, helped fuel his desire to acquire the social-media company Twitter turned X in late 2022.

For the full commentary see:

Tim Higgins. “His Musings Fuel Musk’s Nightmares.” The Wall Street Journal (Monday, May 13, 2024): B3.

(Note: ellipses added.)

(Note: the online version of the commentary has the date May 11, 2024, and has the title “The Man Whose Musings Fuel Elon Musk’s Nightmares.” The last two ellipses above indicate where I omit sentences that appeared in the longer online version, but not in the print version.)

The Saad book that has influenced Elon Musk is:

Saad, Gad. Parasitic Mind: How Infectious Ideas Are Killing Common Sense. New York: Regnery Publishing, 2020.

Bacteria Can Be Genetically Reprogrammed to Cure Cancer Tumors in Mice

Reprograming bacteria to cure cancer tumors is a novel and plausible approach, but there are many other novel and plausible approaches. Cancer is a complicated and diverse disease; maybe we will eventually see “cancer” as many different diseases. We have too much uncertainty to mandate one centrally planned approach. Plus citizens have the right to keep the money they earn and to choose how to spend that money. We should keep taxation and regulations low so that diverse funders can follow their judgements to fund diverse approaches.

(p. D3) Scientists have used genetically reprogrammed bacteria to destroy tumors in mice. The innovative method one day may lead to cancer therapies that treat the disease more precisely, without the side effects of conventional drugs.

The researchers already are scrambling to develop a commercial treatment, but success in mice does not guarantee that this strategy will work in people. Still, the new study, published on Wednesday in the journal Nature Medicine, is a harbinger of things to come, said Dr. Michael Dougan, an immunologist at Massachusetts General Hospital in Boston.

. . .

Our immune cells can sometimes recognize and destroy cancer cells without assistance. But tumors may hide from the immune system by taking advantage of a gene called CD47.

Normally, the gene makes a protein that studs the surface of red blood cells, a kind of sign that reads, “Don’t Eat Me.” Immune cells see it, and pass by healthy red blood cells.

. . .

In recent years, scientists have been developing antibodies that can attach to CD47 proteins on cancer cells, masking the “Don’t Eat Me” sign. Then the body’s immune cells learn to recognize the cancer cells as dangerous and attack.

. . .

Nicholas Arpaia, an immunologist at Columbia University in New York, and Tal Danino, a synthetic biologist, wondered if they could use bacteria to turn the immune system against cancer cells — but from within tumors, rather than from outside.

. . .

The researchers inserted the nanobody gene into the bacteria, turning them into nanobody factories. Then the team injected five million of the altered microbes into mouse tumors.

The bacteria were also programmed to commit mass suicide. After they established themselves and multiplied, 90 percent of the bacteria ripped themselves apart, spilling out nanobodies. The nanobodies attached to CD47 proteins on the cancer cells, robbing them of their camouflage.

. . .

Dr. Danino co-founded a company, GenCirq, that is exploring using these reprogrammed bacteria to treat cancer. Dr. Arpaia is on the leadership board.

Their goal is to treat some forms of metastatic cancer with a pill of programmed bacteria. In earlier research, Dr. Danino and colleagues showed that bacteria swallowed by mice can reach the liver and invade tumors there.

For the full commentary see:

Carl Zimmer. “Matter; Bacteria, Altered to Destroy Cancer.” The New York Times (Tuesday, July 9, 2019 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the commentary has the date July 3, 2019 [sic], and has the title “Matter; New Weapons Against Cancer: Millions of Bacteria Programmed to Kill.”)

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

Chowdhury, Sreyan, Samuel Castro, Courtney Coker, Taylor E. Hinchliffe, Nicholas Arpaia, and Tal Danino. “Programmable Bacteria Induce Durable Tumor Regression and Systemic Antitumor Immunity.” Nature Medicine 25, no. 7 (July 2019): 1057-63.

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.

The Patterns in Unexpected Cancer Cures Can Yield Actionable Insight

The method for fighting cancer discussed by Gina Kolata in the passages quoted below, is similar to the method that led William Coley to first develop immunotherapy in the late 1800s. Coley searched the archives of his hospital, seeking any cases in which cancer seemed to have been spontaneously cured. When he had a few cases he looked for a common feature that might explain the cures. He found that in each case the patient had a severe viral or bacterial infection. When the patient’s immune system cured them of the infection, it also, as a desirable side-effect, cured them of the cancer. In the case of the rare ovarian discussed below, Dr. Levine hypothesizes that the common feature of the rare single-mutation cancers that can be cured by immunotherapy drugs, is that there is a mutated master gene that turns on and off other genes–creating an abnormal variation that somehow alerts the immune system of the presence of tumor cells that should be attacked. (The article quoted below is now over six years old–I wonder if in those six years Dr. Levine has found evidence to support, modify, or reject his hypothesis?) [My memory is foggy on this, but I think Steven Rosenberg may also have applied a similar method after he encountered a case of spontaneous cancer cure when he was working in a veteran’s hospital early in his career–see Rosenberg and Barry, 1992.]

Notice that the four patients only were cured because they had the courage and boldness to ask their oncologist to try a therapy that the standard protocol said would fail. And notice that the four patients only were cured because they had oncologists who had the courage and boldness to violate accepted protocols. Or maybe something besides courage and boldness explains the oncologists’ actions. Maybe the oncologists were practicing medicine in countries were hospitals, regulatory agencies, and health insurance companies did not exert as much pressure to follow the protocol as is exerted in the United States? (I wonder if there is enough information publicly available to check this possibility.)

Notice that instead of searching a dusty archive, Levine joined a patient ovarian cancer Yahoo discussion group. Patients were trying to be in control of their cancers, and unlike some doctors, Levine had the humility to think he could learn from what these activist patients reported. Citizen science is a resource to be used, not a distraction to be tamped down or ridiculed. [Amy Dockser Marcus defends citizen science, and gives an extended example, in her We the Scientists.]

Finally note that the method pursued by Coley and Levine can yield genuine actionable knowledge. Randomized double-blind clinical trials are not the only sources of knowledge.

Gina Kolata has written many thought-provoking articles. I hope to follow-up on this one sometime.

(p. D1) No one expected the four young women to live much longer. They had an extremely rare, aggressive, and fatal form of ovarian cancer. There was no standard treatment.

The women, strangers to one another living in different countries, asked their doctors to try new immunotherapy drugs that had revolutionized treatment of cancer. At first, they were told the drugs were out of the question — they would not work against ovarian cancer.

Now it looks as if the doctors were wrong. The women managed to get immunotherapy, and their cancers went into remission. They returned to work; their lives returned to normalcy.

. . .

“We need to study the people who have a biology that goes against the conventional generalizations.”

Four women hardly constitutes a clinical trial. Still, “it is the exceptions that give you the best insights,” said Dr. Drew Pardoll, who directs the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.

The cancer that struck the young women was hypercalcemic small cell ovarian cancer, which typically occurs in a woman’s teens or 20s. It is so rare that most oncologists never see a single patient with it.

. . .

(p. D3) Women with this form of ovarian cancer were sharing news and tips online in a closed Yahoo group. Dr. Levine asked to become part of the group and began joining the discussions. There he discovered patients who had persuaded doctors to give them an immunotherapy drug, even though there was no reason to think it would work.

The women reported that their tumors shrank immediately.

. . .

Lung cancer, a genetic type of colorectal cancer and melanoma have huge numbers of mutations, and immunotherapy drugs often are successful in treating them. Cancers of the prostate, pancreas, breast, ovaries — and most other tumors — carry few mutations.

“These are the cancers that rarely respond,” Dr. Pardoll said.

The idea that the drugs might work against something like hypercalcemic ovarian cancer, which is fueled by just one genetic mutation, just made no sense.

“For the vast majority of cancers, there is an amazingly clean correlation between response to therapy and mean mutational load,” Dr. Pardoll said.

. . .

And then came a handful of women with a rare ovarian cancer. Oriana Sousa, 28, a psychologist in Marinha Grande, Portugal, was one of them.

She found out she had cancer in December 2011.

. . .

For the next four years, Ms. Sousa’s doctors tried to control the cancer, giving her rounds of chemotherapy, radiotherapy and surgery. But every time, new tumors emerged.

. . .

Things are different now. In 2015, she finally persuaded a doctor to give her an immunotherapy drug, nivolumab. Immediately, her tumors shrank and continued shrinking as she continued with the drug — so much that her doctors now say she has no evidence of disease. Life has returned to normal.

. . .

What saved her? Dr. Eliezer M. Van Allen, a cancer researcher at Dana-Farber Cancer Institute, has come across one clue.

He found that a gene mutated in kidney cancer was sort of a master regulator of other genes, controlling which were turned on and when. But the regulated genes were normal and did not produce proteins that the immune system might recognize as abnormal.

Nonetheless, patients responding to immunotherapy were the ones with the master gene mutation. “We saw this result and weren’t sure what to make of it,” he said.

Dr. Levine and his colleagues found the same phenomenon in patients with hypercalcemic ovarian cancers. One explanation, he and Dr. Van Allen said, is that the immune system may recognize that cells in which genes are erratically turning on and off are dangerous and should be destroyed.

“That is strictly hypothesis,” Dr. Levine cautioned.

For the full story see:

Gina Kolata. “Cured Unexpectedly.” The New York Times (Tuesday, February 20, 2018 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Feb. 19, 2018 [sic], and has the title “Doctors Said Immunotherapy Would Not Cure Her Cancer. They Were Wrong.”)

The academic article co-authored by Dr. Levine that reports on the remission of a rare ovarian cancer in four women is:

Jelinic, Petar, Jacob Ricca, Elke Van Oudenhove, Narciso Olvera, Taha Merghoub, Douglas A. Levine, and Dmitriy Zamarin. “Immune-Active Microenvironment in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Rationale for Immune Checkpoint Blockade.” Journal of the National Cancer Institute 110, no. 7 (2018): 787-90.

The book by Marcus that I praise above is:

Marcus, Amy Dockser. We the Scientists: How a Daring Team of Parents and Doctors Forged a New Path for Medicine. New York: Riverhead Books, 2023.

Rosenberg’s encounter with a case of spontaneous cancer cure, that I mention above, can be found somewhere early in:

Rosenberg, Steven A., and John M. Barry. The Transformed Cell: Unlocking the Mysteries of Cancer. New York: G.P. Putnam’s Sons, 1992.