Category: Methodology

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.)

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.

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.

Government Gave “40 Years of Seriously Incorrect Advice” on Trans Fats

The government’s advice often turns out to be wrong. That is an added argument for not giving the government the power to enforce its advice through mandatory regulations. (“Added” to the fundamental argument based the right to free choice.)

[In May 2021 Nicholas Wade, the author of the review quoted below, showed enormous courage in being one of the first few to risk cancelation by presenting a cogent case that Covid leaked from a Wuhan lab.]

(p. C9) Rachel Carson rightly complained in “Silent Spring” that farmers were sloshing far too many harmful pesticides into the environment. But she took aim at the wrong one. DDT, a mild and enormously effective pesticide, helped rid the United States of malaria and its benefits, if more discriminately pursued, could have outweighed its costs.

The overstrict verdict against DDT is an instance of the harms that can ensue when scientific evidence is ignored. This and other cases described by Paul A. Offit in “Pandora’s Lab: Seven Stories of Science Gone Wrong” raise provocative questions about the reasons that science is misused in modern society.

. . .

Another case of medical advice based on insufficient data is that of dietary fat. As Dr. Offit tells the story, in the 1970s the government advised cutting down on fat consumption. In the 1980s the message changed. Unsaturated fats were good; only saturated fats were bad: Eat margarine, not butter. But then it turned out that unsaturated fats came in two forms, known to chemists as “cis” and “trans,” and that “trans fats” were appallingly active promoters of heart disease. Margarine and hydrogenated vegetable cooking oils, whose use had been encouraged, were rich in trans fats. After 40 years of seriously incorrect advice, trans fats were mostly eliminated from the American diet only in 2012.

. . .

Besides his overconfidence in the checking mechanisms of science, Dr. Offit goes too easy on the motives of those who abuse science. Environmentalists, for instance, are interested in achieving political results, not in distracting scientific caveats and uncertainties, which they do their best to suppress. It is their propensity to take everything to excess that leads to obscurantist positions, such as irrational fear of genetically modified crops.

For the full review see:

Nicholas Wade. “A Little Knowledge.” The Wall Street Journal (Saturday, April 8, 2017 [sic]): C9.

(Note: ellipses added.)

(Note: the online version of the review was updated April 7, 2017 [sic], and has the same title as the print version.)

The book under review is:

Offit, Paul A. Pandora’s Lab: Seven Stories of Science Gone Wrong. Washington, D.C.: National Geographic, 2017.

Potential Malaria Breakthrough Drug Forgotten and Now Ignored Due to Its Chemical Relative and Its Venue of Invention

Progress in science, like progress everywhere, is not inevitable. Progress often requires champions or entrepreneurs to persist in overcoming obstacles. In the case of DFDT, the obstacles arise due to the drug’s association with the chemical DDT and with Nazi Germany, the first of which is unjustly reviled and the second of which is justly reviled. But DFDT should not be judged by either its relatives or its venue of origins It should be judged by its efficacy against malaria, and by its effects, if any, on the environment.

(p. D1) In postwar Allied intelligence reports examined by Dr. Ward and his colleagues, German scientists claimed their insecticide, now called DFDT, was more effective than DDT. Allied officials dismissed those assertions as fanciful, especially given the deplorable behavior of Hoechst, the German chemical manufacturer that developed the insecticide, during the war. The company had forced residents of countries occupied by Germany to work in its factories, and it tested drugs on concentration camp prisoners.

The insecticide was forgotten for decades.

Now, work by Dr. Ward and his colleagues, reported this month [Oct. 2019] in an article in the Journal of the American Chemical Society, appears to corroborate the German claims. The forgotten compound killed mosquitoes in as little as one-fourth the time as DDT.

. . .

(p. D4) Conceivably the more lethal DFDT could be used in even smaller, possibly safer doses. A new option could allow public health officials to rotate insecticides and thwart the resistance to DDT in many mosquitoes today.

“It’s exciting and desperately needed,” said Duane J. Gubler, an emeritus professor in the emerging infectious diseases program at Duke University and the National University of Singapore Graduate Medical School. He was not involved in the study.

But will anyone today risk the time and money needed to determine whether DFDT could be a safe and effective tool against malaria as well as other mosquito-borne diseases like Zika, dengue and yellow fever?

“Donors, governments, they just don’t want the backlash, even if it’s not wholly justified,” said Bart Kahr, Dr. Ward’s colleague at N.Y.U. and an author of the paper.

. . .

The N.Y.U. chemists started the research with no interest in insecticides whatsoever.

They were studying materials that crystallize in a twisted helical pattern. One of the ways to identify such molecules is to scan the internet for images of crystals made by hobbyists. DDT, they found, exhibited the characteristic pinwheel gradients of a helical crystal when illuminated with polarized light.

Jingxiang Yang, a postdoctoral researcher at N.Y.U., started growing DDT crystals and found not only the expected crystals but also more jumbled, chaotic patterns.

“There was some organized and some crazy,” Dr. Kahr said. “We didn’t expect the other stuff, and that other stuff turned out to be a different arrangement of molecules in the crystal. That form wasn’t known to science.”

That led to the next set of experiments. “Since we have two forms,” Dr. Kahr said, “it was natural to ask, which of these forms was the historical killer of insects?”

It turned out that the chaotic form of DDT is deadlier.

As they were going through early scientific data on DDT, the N.Y.U. chemists found mentions of DFDT.

The compound, difluoro-diphenyl-trichloro-ethane is the same molecule as DDT, except with fluorine atoms replacing two of the chlorines.

The Germans developed DFDT at least in part to avoid paying the licensing fees for DDT to the Swiss. It is also possible that the chemical ingredients for DFDT, although considerably more expensive at the time than those for DDT, may have been more readily available in wartime Germany.

. . .

Dr. Kahr wonders: If DFDT had displaced DDT, would the 1955 push have succeeded in bringing malaria under control before resistance set in? “What if this compound wasn’t forgotten,” he said. “What would the world be like? Science doesn’t go as linearly as the general public thinks it does.”

For the full story see:

Kenneth Chang. “Old Mix To Fight Malaria?” The New York Times (Tuesday, October 22, 2019 [sic]): D1 & D4.

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

(Note: the online version of the story was updated Oct. 22, 2019 [sic], and has the title “A Nazi Version of DDT Was Forgotten. Could It Help Fight Malaria?” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Ward, Kahr, and others, and mentioned above, is:

Zhu, Xiaolong, Chunhua T. Hu, Jingxiang Yang, Leo A. Joyce, Mengdi Qiu, Michael D. Ward, and Bart Kahr. “Manipulating Solid Forms of Contact Insecticides for Infectious Disease Prevention.” Journal of the American Chemical Society 141, no. 42 (2019): 16858-64.

The Efficacy of Personalized Drugs Designed for Only One Patient Cannot Be Tested by Randomized Double-Blind Clinical Trials (RCTs)

We know that there are times when therapies work for some patients, but not for others. But clinical trials often do not account for such differences. If the effects of the new drug are not widespread enough among the general population, the trial will be deemed a failure, and the F.D.A. will not allow the drug to be taken even by the patients who would have benefitted from it. Maybe the solution is liberty. Allow physicians liberty on what therapies to suggest, and patients liberty on what therapies to try. This especially makes sense when the disease is dire and no effective therapy is yet widely known.

Many predict that we are moving toward personalized medicine. We need less regulation and more liberty so personalized medicine can progress, and more patients can be more quickly cured of more diseases. We need a sense of urgency in requesting liberty.

(p. D3) A new drug, created to treat just one patient, has pushed the bounds of personalized medicine and has raised unexplored regulatory and ethical questions, scientists reported on Wednesday [Oct. 9, 2019].

The drug, described in The New England Journal of Medicine, is believed to be the first “custom” treatment for a genetic disease. It is called milasen, named after the only patient who will ever take it: Mila (mee-lah) Makovec, who lives with her mother, Julia Vitarello, in Longmont, Colo.

. . .

Ms. Vitarello . . . set up Mila’s Miracle Foundation and was appealing for donations on GoFundMe. So, she began fund-raising in earnest, eventually raising $3 million for a variety of research efforts.

Dr. Yu’s team oversaw development of the drug, tested it in rodents, and consulted with the Food and Drug Administration. In January 2018, the agency granted permission to give the drug to Mila. She got her first dose on Jan. 31, 2018.

With continued treatments, the number of seizures has diminished so much that the girl has between none and six a day, and they last less than a minute.

Milasen is believed to be the first drug developed for a single patient (CAR-T cancer therapies, while individualized, are not drugs). But the path forward is not clear, Dr. Yu and his colleagues acknowledged.

. . .

. . . how might a custom drug’s efficacy might be evaluated, and how should regulators weigh the urgency of the patient’s situation and the number of patients who could ultimately be treated.

For the full story see:

Gina Kolata. “Drug Designed for One Raises Many Questions.” The New York Times (Tuesday, October 15, 2019 [sic]): D3.

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

(Note: the online version of the story has the date Oct. 9, 2019 [sic], and has the title “Scientists Designed a Drug for Just One Patient. Her Name Is Mila.” Where the more detailed online version differs from the print version, the passages quoted above follow the print [sic] version.)

The academic article co-authored by Dr. Yu that reports on the personalized drug milasen is:

Kim, Jinkuk, Chunguang Hu, Christelle Moufawad El Achkar, Lauren E. Black, Julie Douville, Austin Larson, Mary K. Pendergast, Sara F. Goldkind, Eunjung A. Lee, Ashley Kuniholm, Aubrie Soucy, Jai Vaze, Nandkishore R. Belur, Kristina Fredriksen, Iva Stojkovska, Alla Tsytsykova, Myriam Armant, Renata L. DiDonato, Jaejoon Choi, Laura Cornelissen, Luis M. Pereira, Erika F. Augustine, Casie A. Genetti, Kira Dies, Brenda Barton, Lucinda Williams, Benjamin D. Goodlett, Bobbie L. Riley, Amy Pasternak, Emily R. Berry, Kelly A. Pflock, Stephen Chu, Chantal Reed, Kimberly Tyndall, Pankaj B. Agrawal, Alan H. Beggs, P. Ellen Grant, David K. Urion, Richard O. Snyder, Susan E. Waisbren, Annapurna Poduri, Peter J. Park, Al Patterson, Alessandra Biffi, Joseph R. Mazzulli, Olaf Bodamer, Charles B. Berde, and Timothy W. Yu. “Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1644-52.

An accompanying editorial commenting on the regulatory challenges raised by personalized drugs like milasen is:

Woodcock, Janet, and Peter Marks. “Drug Regulation in the Era of Individualized Therapies.” New England Journal of Medicine 381, no. 17 (Oct. 9, 2019): 1678-80.

When the Highly Restrictive Enrollment Criteria for Clinical Trials Steal Hope from the Innocently Desperate, It “Just Feels Unjust”

Muscular dystrophy is sometimes called “Duchenne.” The full name of the disease is “Duchenne muscular dystrophy.” When I was a student at Monroe elementary school a classmate named Frank Goldsberry played on the basketball team. In high school he was in a wheel chair with muscular dystrophy. When the high school principle, Howard Crouch, proposed to do away with the academic honor of valedictorian on the ground that there was some arbitrariness in who received it, I argued that to do would be to diminish the honor given to academic achievement. Crouch relented. It turned out that our valedictorian was Frank Goldsberry. He died a few years later in his early 20s. Frank’s father told my mother that Frank was grateful to me for speaking up. Howard Crouch had a point, but I am glad that after working hard under dire circumstances, Frank received the award.

The F.D.A. should stop mandating randomized double-blind clinical trials (RCTs) so that those who have muscular dystrophy can seek any therapy that they, their parents, and their physicians believe has promise. Not everyone will be cured, but we will learn what works through a Bayesian process of trial and error. More parents and boys will be allowed to hold on to hope.

(p. D1) Lucas was 5 before his parents, Bill and Marci Barton of Grand Haven, Mich., finally got an explanation for his difficulties standing up or climbing stairs. The diagnosis: muscular dystrophy.

Mr. Barton turned to Google.

“The first thing I read was, ‘no cure, in a wheelchair in their teens, pass in their 20s,” Mr. Barton said. “I stopped. I couldn’t read any more. I couldn’t handle it.”

Then he found a reason to hope. For the first time ever, there are clinical trials — nearly two dozen — testing treatments that might actually stop the disease.

The problem, as Mr. Barton soon discovered, is that the enrollment criteria are so restrictive that very few children qualify. As a result, families like the Bartons often are turned away.

. . .

Ryan and Brooke Saalman know how hard it can be to know what to do. “We did a lot of praying,” said Ms. Saalman, mother of two boys with Duchenne in Columbus, Ga.

They decided to enroll their oldest son, Jacob, 6, in a trial of a highly experimental drug.

. . .

. . . they discovered that gene therapy may be irreversible. And if it didn’t work, Ja-(p. D3)cob would be ineligible for an even more promising approach in the future: gene editing, to snip out the deadly mutation that causes Duchenne, an effort now in preclinical development.

. . .

The Bartons found out about a gene-therapy trial at Nationwide Children’s Hospital in Columbus, Ohio, testing a treatment by Sarepta Therapeutics.

They watched a miraculous video of a little boy struggling to walk up a flight of stairs before treatment — and then doing it easily afterward.

“This was what we were hoping for,” Mr. Barton said.

Lucas was the right age, and he seemed to qualify. But testing showed that he carries antibodies to the virus used to deliver the treatment. It would not work for him.

The Bartons were drained, devastated. And for now, there is no other trial that Lucas qualifies for.

“I had my put my hopes into this,” Mr. Barton said. “It was the miracle.”

Dr. Jeffrey Bigelow, a neurologist, and his wife, Alexis Bigelow, of Millcreek, Utah, hoped against hope that their son Henri, 8, would qualify for the only gene therapy trial that will accept boys his age.

Then the Bigelows found out that enrollees of Henri’s age have to be able to lie down and then stand up with their hands at their sides in less than 10 seconds.

It took Henri 10 seconds to do that last spring, when he was evaluated for another trial. Now it would probably take him 20 seconds, his father said.

“It feels like Henri is being punished for losing the ability to stand up from the ground too soon,” Dr. Bigelow said.

He also worries about older boys with Duchenne who are lucky enough to still walk. They are shut out from the trial because they are not yet in wheelchairs. And other trials won’t accept boys that old.

“These are boys who, like Henri, desperately need the treatment, and if they don’t get it in the next one to two years, likely will be confined to a wheelchair, to never walk again,” Dr. Bigelow said.

“This just feels unjust.”

For the full story see:

Gina Kolata. “One Shot To Qualify For Hope.” The New York Times (Tuesday, March 26, 2019 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date March 25, 2019 [sic], and has the title “For Many Boys With Duchenne Muscular Dystrophy, Bright Hope Lies Just Beyond Reach.”)

Rigid Guidelines Don’t Allow for Individualizing Treatment and Discount the Doctor’s Clinical Judgment

The criticism of the Clovers sepsis clinical trial is that the the treatment and placebo arms of the trial each require rigid adherence to a protocol, and such adherence rules out personalizing individual treatment based on individual differences among patients and doctors’ clinical judgment based on past experiences. That criticism seems plausible and also seems to apply, not just to the Clovers sepsis clinical trial, but to all< randomized double-blind clinical trials.

(p. D1) A large government trial comparing treatments for a life-threatening condition called sepsis is putting participants at risk of organ failure and even death, critics charge, and should be immediately shut down.

A detailed analysis of the trial design prepared by senior investigators at the National Institutes of Health Clinical Center in Bethesda, Md., concluded that the study “places seriously ill patients at risk without the possibility of gaining information that can provide benefits either to the subjects or to future patients.”

In a letter to the federal Office for Human Research Protection, representatives of Public Citizen’s Health Research Group compared the study, called Clovers, to “an experiment that would be conducted on laboratory animals.”

“The human subjects of the Clovers trial, as designed and currently conducted, are unwitting guinea pigs in a physiology experiment,” Dr. Michael Carome and Dr. Sidney M. Wolfe wrote in their letter.

Begun in March, Clovers is funded by the N.I.H. — despite the criticism of its own investigators — and aims to enroll 2,320 pa-(p. D3)tients at 44 hospitals around the country.

. . .

At issue is whether patients participating in Clovers are being given treatment that deviates from usual care — so much so that lives may be endangered by the research.  . . .

When patients experience septic shock, current guidelines call for raising blood pressure by administering fluids within the first three hours of care, and then administering vasopressors within the first six hours if patients do not respond to fluids.

Vasopressors can be administered early on, during or after the infusion of fluids; a new treatment guideline for hospitals says the drugs should be started within the first hour if patients aren’t responding to intravenous fluids.

Many physicians have been critical of rigid guidelines like this one because they don’t allow for individualizing treatment and appear to discount the doctor’s clinical judgment.

Both fluids in large amounts and vasopressors can cause serious complications, but when a patient’s condition continues to deteriorate, doctors use both interventions, adjusting them depending on the severity of illness.

They generally start with fluids, which in small amounts are considered less toxic than vasopressors.

But participants in Clovers are randomly assigned to a “liberal fluids” group who receive large infusions of fluids in a very short time but limits the use of vasopressors, or to a “restrictive fluids” group in which fluids are minimized and drug treatment begun earlier.

For the full story see:

Roni Caryn Rabin. “Critics Demand Halt of a Sepsis Trial.” The New York Times (Tuesday, September 25, 2018 [sic]): D1 & D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Sept. 24, 2018 [sic], and has the title “Trial by Fire: Critics Demand That a Huge Sepsis Study Be Stopped.”)

The Number of Alzheimer’s Patients Is Too Few to Populate the Many Promising Clinical Trials

When the F.D.A. mandates randomized double-blind clinical trials (RCTs) be successfully performed before allowing the use of a new drug, it also mandates that diverse promising drugs will never be tested. Some of those drugs might help or even cure Alzheimer’s. The reason that some diverse promising drugs will never be tested, as explained by Gina Kolata in the passage quoted below, is that there are too few diagnosed and willing Alzheimer’s patients to conduct the number and kind of RCTs that the government mandates, for all the promising drugs under development. What is the alternative to mandated RCTs? Allow physicians to prescribe drugs that have a promising rationale. If their patients benefit the physicians will continue to prescribe the drug and they will tell their colleagues.

(p. D1) The task facing Eli Lilly, the giant pharmaceutical company, sounds simple enough: Find 375 people with early Alzheimer’s disease for a bold new clinical trial aiming to slow or stop memory loss.

There are 5.4 million Alzheimer’s patients in the United States. You’d think it would be easy to find that many participants for a trial like this one.

But it’s not. And the problem has enormous implications for treatment of a disease that terrifies older Americans and has strained families in numbers too great to count.

The Global Alzheimer’s Platform Foundation, which is helping recruit participants for the Lilly trial, estimates that to begin finding participants, it will have to inform 15,000 to 18,000 people in the right age groups about the effort.

Of these, nearly 2,000 must pass the initial screening to be selected for further tests to see if they qualify.

Just 20 percent will meet the criteria to enroll in Lilly’s trial: They must be aged 60 to 89, have mild but progressive memory loss for at least six months, and have two types of brain scans showing Alzheimer’s is underway.

Yet an 80 percent screening failure rate is typical for Alzheimer’s trials, said John Dwyer, president of the foundation. There is just no good way to quickly diagnose the disease.

The onerous process of locating just 375 patients illustrates a grim truth: finding patients on whom to test new Alzheimer’s treatments is becoming an insurmountable obstacle — no matter how promising the trial.

With brain scans, lab tests and memory tests, the cost per diagnosis alone is daunting — as much as $100,000 for each person who ends up enrolled in a trial, Mr. Dwyer said — even before they begin the experimental treatment.

Complicating the problem, the number of trials has exploded in recent years. There (p. D4) are more than 100 Alzheimer’s studies looking for a whopping 25,000 participants, Mr. Dwyer said.

To begin filling them all, 37.5 million patients in the right age group would first have to be informed. Ten percent would be referred to a trial site for screening.

Just 4 percent will move forward with an evaluation, and of these, just over 17 percent will drop out, given the current rate, leaving roughly 125,000 to be screened. And with an 80 percent screening failure rate, that leaves 25,000 participants of the 37.5 million who were first informed.

The numbers make it clear: There’s no way scientists are going to find 25,000 participants for all of the Alzheimer’s trials that have been approved.

“The irony is that the science has never been more promising,” Mr. Dwyer said. “How many promising drugs will be abandoned or their evaluation seriously delayed? Some good science is going to be left on cutting-room floor.”

For the full story see:

Gina Kolata. “Alzheimer’s Trials Hit a Roadblock.” The New York Times (Tuesday, July 24, 2018 [sic]): D1 & D4.

(Note: the online version of the story has the date July 23, 2018 [sic], and has the title “For Scientists Racing to Cure Alzheimer’s, the Math Is Getting Ugly.”)

Scientists Invest Much Money and Time to Develop Machines Able to Sniff as Well as a Dog

Seven years have passed since the article quoted below predicted that sniffing devices would be available to clinicians in three to five years. I believe the prediction was premature. In the meantime, we should be making more and better use of dog noses to sniff out disease.

(p. D5) But not every physician’s nose is a precision instrument, and dogs, while adept at sniffing out cancer, get distracted. So researchers have been trying for decades to figure out how to build an inexpensive odor sensor for quick, reliable and noninvasive diagnoses.

. . .

“You’re seeing a convergence of technology now, so we can actually run large-scale clinical studies to get the data to prove odor analysis has real utility,” said Billy Boyle, co-founder and president of operations at Owlstone, a manufacturer of chemical sensors in Cambridge, England.

Mr. Boyle, an electronics engineer, formed the company with two friends in 2004 to develop sensors to detect chemical weapons and explosives for customers, including the United States government. But when Mr. Boyle’s girlfriend and eventual wife, Kate Gross, was diagnosed with colon cancer in 2012, his focus shifted to medical sensors, with an emphasis on cancer detection.

Ms. Gross died at the end of 2014. That she might still be alive if her cancer had been detected earlier, Mr. Boyle said, continues to be a “big motivator.”

. . .

A similar diagnostic technology is being developed by an Israeli chemical engineer, Hossam Haick, who was also touched by cancer.

“My college roommate had leukemia, and it made me want to see whether a sensor could be used for treatment,” said Mr. Haick, a professor at Technion-Israel Institute of Technology in Haifa. “But then I realized early diagnosis could be as important as treatment itself.”

. . .

In the United States, a team of researchers from the Monell Chemical Senses Center and the University of Pennsylvania received an $815,000 grant in February [2017] from the Kleberg Foundation to advance work on a prototype odor sensor that detects ovarian cancer in samples of blood plasma.

. . .

“We are trying to make the device work the way we understand mammalian olfaction works,” said Charlie Johnson, director of the Nano/Bio Interface Center at the University of Pennsylvania, who is leading the fabrication effort. “DNA gives unique characteristics for this process.”

In addition to these groups, teams in Austria, Switzerland and Japan also are developing odor sensors to diagnose disease.

“I think the fact that you’re seeing so much activity both in commercial and academic settings shows that we’re getting a lot closer,” said Cristina Davis, a biomedical engineer and professor at the University of California, Davis, who also is helping to develop an odor sensor to diagnose disease.

“My estimate is it’s a three- to five-year time frame” before such tools are available to clinicians, she added.

For the full story see:

Kate Murphy. “The Race to Sniff Out Disease.” The New York Times (Tuesday, May 2, 2017 [sic]): D5.

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

(Note: the online version of the story has the date May 1, 2017 [sic], and has the title “One Day, a Machine Will Smell Whether You’re Sick.”)

Ozempic Profits Poured into Massive Supercomputer Meant to Power AI for Future Drug Development

I think AI is currently being oversold. But I am very ignorant and could be wrong, so I favor a diversity of privately-funded bets on what will work to bring us future breakthrough innovations.

(p. B2) Two of the world’s most important companies are now in a partnership born from the success of their most revolutionary products. The supercomputer was built with technology from Nvidia—and money from the Novo Nordisk Foundation. The charitable organization has become supremely wealthy as the largest shareholder in Novo Nordisk, which means this project was made possible by the breakthrough drugs that have sent the Danish company’s stock price soaring.

To put it another way, it’s the first AI supercomputer funded by Ozempic.

It was named Gefion after the goddess of Norse mythology who turned her sons into oxen so they could plow the land that would become Denmark’s largest island.

. . .

Whatever you call it, Gefion is a beast. It is bigger than a basketball court. It weighs more than 30 tons. It took six months to manufacture and install. It also required an investment of $100 million.

. . .

When it’s fully operational, the AI supercomputer will be available to entrepreneurs, academics and scientists inside companies like Novo Nordisk, which stands to benefit from its help with drug discovery, protein design and digital biology.

For the full commentary see:

Ben Cohen. “It’s a Giant New Supercomputer That Might Transform an Entire Country.” The Wall Street Journal (Saturday, Nov. 2, 2024): B2.

(Note: ellipses added.)

(Note: the online version of the commentary has the date November 1, 2024, and has the title “Science of Success; The Giant Supercomputer Built to Transform an Entire Country—and Paid For by Ozempic.”)