Science – artdiamondblog.com

Tim Friede’s “Daredevilry” in Taking 650 Venom Injections and 200 Poisonous Snake Bites to Help Create a Universal Antivenom “for Humanity”

Back during Covid, over 38,000 adults volunteered to participate in a “challenge” clinical trial of the new vaccines, but such trials were not allowed. In a challenge trial each participant receives the vaccine and then is exposed to the disease. Phase 3 trials for efficacy can be completed much more quickly, with many fewer participants, and at much lower costs, if the trials are “challenge” trials.

We allow people the freedom to dangerous actions for fun or excitement, or to help humanity, like Tim Friede (below) injecting snake venom and letting snakes bite him. Why then did we not allow challenge trials with the Covid vaccine?

Note on another issue, that the researchers are planning in their next step to test their antivenom on dogs who are bitten by snakes. This is a good example of my ideal use of dogs in medical research–where the trial aims at benefits for both the humans AND the dogs.

(p. A1) Over nearly 18 years, the man, Tim Friede, 57, injected himself with more than 650 carefully calibrated, escalating doses of venom to build his immunity to 16 deadly snake species. He also allowed the snakes — mostly one at a time, but sometimes two, . . . — to sink their sharp fangs into him about 200 times.

This bit of daredevilry (one name for it) may now help to solve a dire global health problem. More than 600 species of venomous snakes roam the earth, biting as many as 2.7 million people, killing about 120,000 people and maiming 400,000 others — numbers thought to be vast underestimates.

In Mr. Friede’s blood, scientists say they have identified antibodies that are capable of neutralizing the venom of multiple snake (p. A19) species, a step toward creating a universal antivenom, they reported on Friday [May 2, 2025] in the journal Cell.

“I’m really proud that I can do something in life for humanity, to make a difference for people that are 8,000 miles away, that I’m never going to meet, never going to talk to, never going to see, probably,” said Mr. Friede, who lives in Two Rivers, Wis., where venomous snakes are not much of a threat.

. . .

“This is a bigger problem than the first world realizes,” said Jacob Glanville, founder and chief executive of Centivax, a company that aims to produce broad-spectrum vaccines, and lead author on the study.

Dr. Glanville and his colleagues found that two powerful antibodies from Mr. Freide’s blood, when combined with a drug that blocks neurotoxins, protected mice from the venom of 19 deadly snake species of a large family found in different geographical regions.

This is an extraordinary feat, according to experts not involved in the work. Most antivenoms can counter the venom from just one or a few related snake species from one region.

The study suggests that cocktails of antitoxins may successfully prevent deaths and injuries from all snake families, said Nicholas Casewell, a researcher at the Liverpool School of Tropical Medicine in England.

. . .

There were other mishaps — accidental bites, anaphylactic shocks, hives, blackouts. Mr. Friede describes himself as a nondegree scientist, but “there’s no college in the world that can teach you how to do it,” he said. “I was doing it on my own as best I could.”

Two teams of scientists sampled Mr. Friede’s blood over the years, but neither project led anywhere. By the time he met Dr. Glanville, in 2017, he was nearly ready to give up.

Dr. Glanville had been pursuing what scientists call broadly acting antibodies as the basis for universal vaccines against viruses. He grew up in a Maya village in the Guatemala highlands, and became intrigued by the possibility of using the same approach for universal antivenom.

. . .

The researchers next plan to test the treatment in Australia in any dogs that are brought into veterinary clinics for snakebites. They are also hoping to identify another component, perhaps also from Mr. Friede’s blood, that would extend full protection to all 19 snake species that were subjects of the research.

Mr. Friede himself is done now, however. His last bite was in November 2018, from a water cobra. He was divorced — his wife and children had moved out. “Well, that’s it, enough is enough,” he recalled thinking.

He misses the snakes, he said, but not the painful bites. “I’ll probably get back into it in the future,” he said. “But for right now, I’m happy where things are at.”

For the full story see:

Apoorva Mandavilli. “Man of 200 Snake Bites May Be the Antivenom.” The New York Times (Saturday, May 3, 2025): A1 & A19.

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

(Note: the online version of the story has the date May 2, 2025, and has the title “Universal Antivenom May Grow Out of Man Who Let Snakes Bite Him 200 Times.”)

The academic article in the journal Cell mentioned above is:

Glanville, Jacob, Mark Bellin, Sergei Pletnev, Baoshan Zhang, Joel Christian Andrade, Sangil Kim, David Tsao, Raffaello Verardi, Rishi Bedi, Sindy Liao, Raymond Newland, Nicholas L. Bayless, Sawsan Youssef, Ena S. Tully, Tatsiana Bylund, Sujeong Kim, Hannah Hirou, Tracy Liu, and Peter D. Kwong. “Snake Venom Protection by a Cocktail of Varespladib and Broadly Neutralizing Human Antibodies.” Cell 188 (2025): 1-18.

Muriel Bristol Was Allowed to Act on What She Knew but Was Unable to Prove or Explain

Muriel Bristol knew that tea tasted better when the milk was poured in first, than when it was poured in after the tea. She knew it but couldn’t prove it and didn’t know why it was true. The world is better when more of us, more often, can act on what we know, but what we can neither prove nor explain. Too often regulations restrict the actions of entrepreneurs to what they can prove and explain, e.g., in the firing of employees.

This slows and reduces efficiency and innovation (not to mention freedom).

(p. C8) [Adam] Kucharski, a mathematically trained epidemiologist, says that the rigor and purity of mathematics has imbued it with extraordinary rhetorical power. “In an uncertain world, it is reassuring to think there is at least one field that can provide definitive answers,” he writes. Yet he adds that certainty can sometimes be an illusion. “Even mathematical notions of proof” are “not always as robust and politics-free as they might seem.”

. . .

. . ., proving what is “obvious and simple” isn’t always easy. Kucharski offers the delightful example of Muriel Bristol, a scientist who always put the milk in her cup before pouring her tea, because she insisted it tasted better. In the 1920s, a skeptical statistician designed a blind taste test to see if Bristol could distinguish between cups of milk-then-tea and cups of tea-then-milk. Bristol got all of them right. In 2008, the Royal Society of Chemistry reported that when milk is poured into hot tea, “individual drops separate from the bulk of the milk” and allow “significant denaturation to occur.” The result is a burnt flavor. Eighty years after Bristol was statistically vindicated, she was chemically vindicated too.

For the full review see:

Jennifer Szalai. “Proving It Doesn’t Necessarily Make It True.” The New York Times (Saturday, May 3, 2025): C8.

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

(Note: the online version of the review has the date April 30, 2025, and has the title “Just Because You Can Prove It Doesn’t Make It True.”)

The book under review is:

Kucharski, Adam. Proof: The Art and Science of Certainty. New York: Basic Books, 2025.

Pasteur Saw That “Germs Were Everywhere in the Air”

The passages quoted below show how Pasteur respected his audience by finding a clear and compelling way to communicate that “germs” float in the air. The essay quoted below is adapted from Zimmer’s recently released Air-Borne book.

In other parts of Air-Borne, Zimmer discusses how the W.H.O. and the C.D.C. ignored the implications of the findings of Pasteur and others, relevant to the air-borne (aerosol) spread of diseases such as Covid-19.

(p. D8) On the evening of April 7, 1864, in an amphitheater filled with Parisian elites, Pasteur stood surrounded by lab equipment and a lamp to project images on a screen. He told the audience it would not leave the soiree without recognizing that the air was rife with invisible germs. “We can’t see them now, for the same reason that, in broad daylight, we can’t see the stars,” he said.

At Pasteur’s command, the lights went out, save for a cone of light that revealed floating motes of dust. Pasteur asked the audience to picture a rain of dust falling on every surface in the amphitheater. That dust, he said, was alive.

Pasteur then used a pump to drive air through a sterile piece of cotton. After soaking the cotton in water, he put a drop under a microscope. He projected its image on a screen for the audience to see. Alongside soot and bits of plaster, they could make out squirming corpuscles. “These, gentlemen, are the germs of microscopic beings,” Pasteur said.

Germs were everywhere in the air, he said — kicked up in dust, taking flights of unknown distances and then settling back to the ground, where they worked their magic of fermentation. Germs broke down “everything on the surface of this globe which once had life, in the general economy of creation,” Pasteur said.

“This role is immense, marvelous, positively moving,” he added.

The lecture ended with a standing ovation. Pasteur’s hunt for floating germs elevated him to the highest ranks of French science.

For the full essay see:

Zimmer, Carl. “He Showed That Germs Floated in Air.” The New York Times (Tuesday, February 18, 2025): D8.

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

(Note: the online version of the essay was updated Feb. 18, 2025, and has the title “Louis Pasteur’s Relentless Hunt for Germs Floating in the Air.”)

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

Zimmer, Carl. Air-Borne: The Hidden History of the Life We Breathe. New York: Dutton, 2025.

90% of Biomedical Articles Are “Either Misleading, Wrong or Completely Fabricated”

The right to health freedom is primarily an ethical issue. But the uncertainty and unreliability of much medical “knowledge” (as argued in the book reviewed in the passages quoted below) seems to strengthen the case for patient self-determination.

(p. A15) The largest repositories of biomedical research in the U.S. and Europe, PubMed and Europe PMC, contain 84 million articles between them, and add a million more each year. According to recent estimates, up to 90% of those papers—75 million total—contain information that’s either misleading, wrong or completely fabricated.

Over the past 20 years, certain branches of science have endured a so-called reproducibility crisis, in which countless papers have been exposed as shoddy if not bogus. Sometimes these revelations are merely embarrassing, but in biomedical research, incorrect publications can cost lives as doctors and drugmakers rely on them to treat patients.

In “Unreliable: Bias, Fraud, and the Reproducibility Crisis in Biomedical Research,” Csaba Szabo—a physician with doctorates in physiology and pharmacology—dissects the ways he’s seen research go wrong in his 30 years in academia and industry: data manipulation, poor experimental design, statistical errors and more.

. . .

The biggest problem, however, lies with scientists who strive to do good work but feel pressured to cut corners. Scientists cannot work without grant money, but of the 70,000 applications the National Institutes of Health receive each year, only 20% get funded. Leading journals reject up to 99% of papers submitted, and only one in 200 doctoral graduates ever becomes a full professor. Even with tenure, professors can suffer salary cuts or have their labs handed to higher-performing colleagues if they don’t keep pulling in cash. Some sadistic research professors even pit their graduate students against each other in “dogfights”—they run the same experiment, but only the first to get results publishes. No wonder researchers massage data or fudge images: Forget “publish or perish.” It’s “fib or forgo your career.”

. . .

Given this tsunami of mistakes, the author points out that cynical types have suggested we treat all biomedical research as fraudulent unless proved otherwise. The cost is staggering: The U.S. wastes tens of billions of dollars annually on useless research, shortening or even costing patient lives. Most scientists can’t even reproduce their own data half the time, and the number of papers retracted rose to 10,000 in 2023 from 500 in 2010.

. . .

Most importantly, Dr. Szabo calls for systematic changes in how science gets done.

. . .

Above all, he despises the broken status quo, where “everybody acts politely . . . keeps their mouths shut, and acts like the whole process is functioning perfectly well.”

For the full review see:

Sam Kean. “Bookshelf; Reaching For Results.” The Wall Street Journal (Tuesday, March 24, 2025): A15.

(Note: ellipses between paragraphs added; ellipsis internal to paragraph, in original.)

(Note: the online version of the review was updated March 24, 2025, and has the title “Bookshelf; ‘Unreliable’: Reaching for Results.”)

The book under review is:

Szabo, Csaba. Unreliable: Bias, Fraud, and the Reproducibility Crisis in Biomedical Research. New York: Columbia University Press, 2025.

Vindication is Sweet, Even 60 Years Too Late

When I was a child my mother would stick an oral thermometer in my mouth. When she returned she would always be annoyed with me, saying that I didn’t have it in right, because my temperature was too low. She would say with irritation: ‘Now this time do it right!’ So I would feel discouraged and would give the thermometer a hard jab into my mouth until it hurt. But my temperature would still be too low.

The story below suggests, decades too late for me, that maybe it wasn’t my fault. Maybe the official mandated “normal” temperature of 98.6 was wrong!

(p. D6) We seem to be getting cooler. Since 1851, when the standard was set at 37 degrees centigrade, or 98.6 Fahrenheit, the average human body temperature has steadily declined.

. . . . The analysis is in eLife.

. . .

. . . improvements in sanitation and improved dental and medical care have reduced chronic inflammation, and the constant temperatures maintained by modern heating and air conditioning have helped lower resting metabolic rates. Today, a temperature of 97.5 may be closer to “normal” than the traditional 98.6.

For the full story see:

Nicholas Bakalar. “Is 98.6 No Longer ‘Normal’?” The New York Times (Tuesday, January 21, 2020): D6.

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

(Note: the online version of the story was updated Jan. 21, 2020 [sic], and has the title “Body Temperature 2.0: Do We Need to Rethink What’s Normal?”)

The academic paper in eLife, mentioned above, is:

Protsiv, Myroslava, Catherine Ley, Joanna Lankester, Trevor Hastie, and Julie Parsonnet. “Decreasing Human Body Temperature in the United States since the Industrial Revolution.” eLife 9 (2020): e49555.

A Nimble Evolving Virus Can Outpace Sluggish Vaccine Clinical Trials

The long time that Phase 3 clinical trials take is a major cost. This is especially true for the poor souls whose dire disease will kill them soon. It is also true, as was the case for the rapidly evolving Covid virus discussed below, where the disease is evolving so fast that it is a moving target.

We should calibrate relative risks. What is the risk from delay? What is the risk from less certainty about efficacy?

When the risks from delay are huge, it makes sense to use quicker, allegedly less certain, sources of knowledge, rather than wait for the allegedly certain results of Phase 3 clinical trials.

(p. A13) WASHINGTON — A panel of independent experts advising the Food and Drug Administration is set to recommend on Tuesday [June 28, 2022] whether to update existing Covid-19 vaccines to target a newer version of the coronavirus in a booster shot that Americans could get in the fall.

The federal government is hoping to improve the vaccine to better boost people’s immunity before a likely resurgence of the virus this winter. But to move that quickly, it may need to abandon the lengthy human trials that have been used to test coronavirus vaccines over the past two years in favor of a faster process that relies more on laboratory tests and animal trials.

The most recent trials with human volunteers have taken five months, even using relatively small groups. But the virus is evolving so quickly that new vaccine formulations are out of date before such trials are even finished.

For the full story see:

Sharon LaFraniere. “Chasing Fast-Evolving Virus, F.D.A. May Move to Update Covid Vaccine.” The New York Times (Tuesday, June 28, 2022 [sic]): A13.

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

(Note: the online version of the story has the date June 27, 2022 [sic], and has the title “F.D.A. May Move Toward Updating Vaccines.”)

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

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

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

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

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

. . .

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

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

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

. . .

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

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

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

For the full story see:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

. . .

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

. . .

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

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

. . .

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

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

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

. . .

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

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

For the full review see:

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

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

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

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

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

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

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

Innovative Research Is More Likely to Come from Small Teams

The incentives and constraints of doing research in medicine make the process very expensive, which leads it increasingly be a large group activity.
The article below suggests that large group research tends to be less innovative. We should reduce the costs by reducing regulations, including the mandate that no drug can be sold without an F.D.A.-approved Phase 3 clinical trial to prove efficacy.

(p. D3) In the largest analysis of the issue thus far, investigators have found that the smaller the research team working on a problem, the more likely it was to generate innovative solutions. . . .

The new research, published on Wednesday [Feb. 13, 2019] in the journal Nature, is the latest contribution from an emerging branch of work known as the science of science — the study of how, when and through whom knowledge advances.

. . .

In the study, a trio of investigators led by James A. Evans, a sociologist at the University of Chicago, mined selections from three vast databases: . . .

. . .

When the team correlated this disruption rating to the size of the group responsible for the project or paper, they found a clear pattern: smaller groups were more likely to produce novel findings than larger ones. Those novel contributions usually took a year or so to catch on, after which larger research teams did the work of consolidating the ideas and solidifying the evidence.

“You might ask what is large, and what is small,” said Dr. Evans. “Well, the answer is that this relationship holds no matter where you cut the number: between one person and two, between ten and twenty, between 25 and 26.”

. . .

Psychologists have found that people working in larger groups tend to generate fewer ideas than when they work in smaller groups, or when working alone, and become less receptive to ideas from outside.

. . .

The new study suggests that a different kind of funding approach may be needed, one that takes more risk and spends the time and money to support promising individuals and small groups, Dr. Evans said.

“Think of it like venture capitalists do,” he said. “They expect a 5 percent success rate, and they try to minimize the correlation between the business they fund. They have a portfolio, one that gives them a higher risk-tolerance level, and also higher payoffs.”

For the full story see:

Benedict Carey. “Is Bigger Better? Not in This Case.” The New York Times (Tuesday, February 19, 2019 [sic]): D3.

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

(Note: the online version of the story has the date Feb. 13, 2019 [sic], and has the title “Can Big Science Be Too Big?”)

The academic article co-authored by Evans is:

Wu, Lingfei, Dashun Wang, and James A. Evans. “Large Teams Develop and Small Teams Disrupt Science and Technology.” Nature 566, no. 7744 (Feb. 2019): 378-82.

Allow Those with Skin in the Game to Help Find Quicker Cures

The New York Times devoted more than two and half full pages to the article that I quote from below. Very very few articles receive that much space. The story is meant to inspire and it does. Linde has a terrible genetic disease, as did her mother and grandmother, as do her two sisters, and as might her two daughters. She is uncredentialled, but determined. She reads scientific articles, gives talks at scientific meetings, creates a foundation to raise funds, and with her sisters gave samples from her skin to create cell lines that can be used for research to find a cure. Linde, both literally and figuratively, has skin in the game.

In the article, victims of the disease wish that there were more clinical trials to test more possible cures. If the price of clinical trials were lower, more of them would be supplied. One way to reduce the price would be for the F.D.A. to only mandate testing for safety, not to mandate testing for efficacy. After all, it was concerns over the safety, not the efficacy, of thalidomide, that first accelerated the F.D.A.’s clinical trial mandates. Testing only for safety (Phase 1 and Phase 2 clinical trials), would hugely reduce the price, resulting ultimately in more and quicker cures.

(p. A1) Linde Jacobs paced back and forth across her bedroom, eyeing the open laptop on the dresser and willing the doctor to appear. Her husband was dropping off their older daughter at school. Their younger daughter was downstairs, occupied by a screen. Linde wanted to be alone when she learned whether she carried the family curse.

Linde’s mother, Allison, had died just four weeks before, after a mutant gene gradually laid waste to her brain. In her 50s, Allison transformed from a joyful family ringleader into an impulsive, deceptive pariah. She drove like a maniac on cul-de-sacs. She pinched strangers, shoplifted craft supplies and stole money from her daughter.

Now, on this morning in September 2021, Linde would find out if she had inherited the same vile genetic mutation.

. . .

The doctor finally popped up on the computer. Wasting no time on pleasantries, she shared her screen and zoomed in on one line of laboratory paperwork: POSITIVE.

. . .

Soon, Linde’s husband, Taylor, pulled into the garage and opened the car door. He could hear her sobbing.

. . .

Linde looked at Taylor. “I don’t want you to feel stuck with me,” she said.

(p. A12) Leaving had never crossed his mind. Allison’s miserable experience, he told Linde, did not have to be hers. “You have all this time,” he said. “Do something about it.”

Even as they spoke, scientists were working on projects that might one day help her. Some had discovered how to cure grave conditions with gene editing. Others were tinkering with patients’ skin cells to test experimental drugs. And pharmaceutical companies were developing new Alzheimer’s therapies, one of which happened to target the rare defect in Linde’s brain.

Linde didn’t know any of that yet. But she decided to take Taylor’s advice. She would use the time she had, somehow, to find influential scientists and make them care about what was happening to her — and what might happen to her girls.

Linde and Taylor scoured the internet for any scrap of hope about treating frontotemporal dementia, or FTD. There was little to read.

Taylor remembered a Netflix documentary about a new way to edit genes. The method, called CRISPR, had cured some children with sickle cell disease. He searched “FTD treatment CRISPR” and found the website of Dr. Claire Clelland, a neurologist at the University of California, San Francisco. She had collected skin cells from patients with FTD, reprogrammed them into neurons and tried to edit the faulty genetic code within.

The website listed a phone number. Taylor called and left a message — a Hail Mary, he figured.

Within a day, Dr. Clelland responded by email. “Happy to help if I can,” she wrote.

. . .

(p. A13) “Could I ask a question?” one young scientist said. How much risk, she wondered, was Linde comfortable taking on an experimental treatment? Editing genes with CRISPR was new, after all, and could come with serious side effects.

“Sign me up, patient zero, sounds good,” Linde said.

“What choice do I have,” she added, “if I don’t want the same future for myself as my mom had, and her mom?”

When she wasn’t working or coaching her daughter’s soccer team, Linde threw herself into the scientific research on MAPT — a niche but growing subfield. The gene provides the instructions for cells to make tau, a protein in the brain.

One day she came across news of a project investigating how tau can go awry. She wrote to the scientist leading the work, Dr. Kenneth Kosik of the University of California, Santa Barbara, describing her family and asking to talk.

Dr. Kosik was sitting in his home office when her note landed in his inbox. “It was the second time in my life that I realized, I’ve got to get back to this person in, like, a nanosecond,” he recalled.

. . .

Dr. Kosik told Linde that an elite group of researchers, known as the Tau Consortium, would gather in Boston in a few months for its annual meeting. Dr. Clelland would be there, as would other “Michael Jordans” in the field. We should try to get you there, he said, so the scientists can be reminded of the human toll of tau-related diseases.

A few weeks later, Linde received an invitation to be the keynote speaker. Jenica and Ashlyn could come, too.

She texted her sisters, “Holy shit.”

One morning in Boston in June 2023, Linde and her sisters got all dolled up, only to arrive in a grand hotel ballroom filled with 100 scientists in oxfords and sneakers.

Dr. Kosik introduced Linde to the members of the Tau Consortium. Too nervous to look anyone in the eye, she stared at a screen showing her slides and read from her prepared remarks.

“You will notice the lack of credentials following my name,” she began. But she said her life had brought her other titles: Caregiver. Jail-Bailer. Carrier. She was the heartbeat, she said, of the cells they studied.

. . .

After the Boston talk, Linde received a flurry of invitations to tell her story. She was interviewed on YouTube by Emma Heming Willis, the wife of the actor Bruce Willis, the most famous person known to have frontotemporal dementia. She came face to face with monkeys that carried MAPT mutations in Madison, Wis. And though she detested the crowds and grime of big cities, she flew to places like Philadelphia and Washington, D.C., to at-(p. A14)tend scientific meetings.

Linde, who by then had moved to River Falls, Wis., always returned home exhausted. But the trips were also fortifying. Learning about the latest research quelled her anxiety — and her husband’s. . . .

During her travels, Linde met other families with MAPT mutations. They were all frustrated by the lack of clinical trials for their genetic glitch, especially because several promising treatments were in the pipeline for other dementia genes. Linde and the others started a global survey of people with MAPT mutations. If an opportunity came along for a clinical trial, they would make it as easy as possible for scientists to find volunteers.

. . .

A few months later, Linde and the group started a nonprofit, called Cure MAPT FTD. They have since found more than 500 people with confirmed or possible MAPT mutations in 10 countries, all of whom have expressed interest in participating in future clinical trials.

In March of this year, Linde got an astonishing offer from Dr. Clelland. Along with collaborators at Washington University and the Neural Stem Cell Institute in New York, she wanted to collect skin cells from Linde and her sisters and turn them into clusters that divide infinitely, known as cell “lines.”

“We propose to make new lines that can be shared with academics and also with industry so that people can do drug screening” and CRISPR projects, Dr. Clelland wrote.

. . .

Based on what happened to Allison and Bev, Linde figures she has at least 10 more years before she starts showing symptoms. But there’s no guarantee; some MAPT carriers begin to change in their 20s. Whenever Linde tells a joke a little too loudly, or has a dulled emotional response to a dramatic event, she worries: Is this tau?

That anxious metronome never shuts off. It compels her to fill any moment of downtime reading the latest study or sending another email. She has spent thousands of dollars and hundreds of unpaid hours on travel. But sometimes, like when she finds herself alone in a hotel room, FaceTiming her daughter about a rough day at school, she questions whether these scientific pursuits are really the best way to run out the clock.

. . .

Dr. Clelland said designing a CRISPR molecule that could precisely excise the MAPT mutation from a cell’s genome was not the hard part. The major unsolved challenge is delivering those molecular scissors into the brain. Still, she and her colleagues at U.C.S.F. have set an ambitious goal of getting MAPT therapy into clinical trials within four years.

For the full story see:

Virginia Hughes. “A Mother’s Race to Beat a Genetic Time Bomb.” The New York Times (Wednesday, December 25, 2024): A1 & A12-A14.

(Note: ellipses added.)

(Note: the online version of the story was updated Jan. 2, 2025, and has the title “Fighting to Avoid Her Mother’s Fate, for Her Daughters’ Sake.” I have omitted a few subhead titles that appear in both the online and print versions.)

For Quicker Cures, Do Not Cancel Those Who See What We Do Not See

Dogs smell odors that we do not smell. They say Eskimos can distinguish 40 or more kinds of snow. Physical differences in biology and differences in past experiences allow some people to perceive what other people miss. We should encourage, not cancel, those who see differently. They can communicate and act on what they see, giving us more cures more quickly.

In the passages quoted below, a case is made that Pasteur’s artistic experiences allowed him to see a structural difference (chirality) in crystals; a difference that turns out to matter for medical drug molecules.

(p. D5) In a paper published last month in Nature Chemistry, Dr. Gal explains how a young Pasteur fought against the odds to articulate the existence of chirality, or the way that some molecules exist in mirror-image forms capable of producing very different effects. Today we see chirality’s effects in light, in chemistry and in the body — even in the drugs we take.

And we might not know a thing about them if it weren’t for the little-known artistic experience of Louis Pasteur, says Dr. Gal.

. . .

As a teenager, Pasteur made portraits of his friends, family and dignitaries. But after his father urged him to pursue a more serious profession — one that would feed him — he became a scientist. At the age of 24 he discovered chirality.

To understand chirality, consider two objects held up before a mirror: a white cue ball from a pool table and your hand. The reflection of the ball is exactly like the original. If you could reach into that mirror, pull out the reflection and cram it inside the original, they’d match up point for point. But if you tried the same thing with your hand, no matter how much you tried, the mirror image would never fit into the original.

At the molecular level some objects are like cue balls, and they are always superimposable. But other things are like hands, and they can never be combined.

. . .

During winemaking, a chemical called tartaric acid builds up on vat walls. In the 18th and 19th centuries, makers of medicine and dyes used this acid.

In 1819, factory workers boiled wine too long and accidentally produced paratartaric acid, which had unique properties that intrigued scientists like Pasteur.

. . .

When studying the paratartaric acid, Pasteur found that it produced two kinds of crystals — one like those found in tartaric acid and another that was the mirror opposite. The crystals were handed, or what the Greeks call chiral (kheir) for hand.

. . .

“Several famous or much more accomplished scientists, some well along their illustrious careers, studied the same molecules, the same substances,” said Dr. Gal. “Realistically you would think they’d have beaten him to the punch, and yet they missed it.”

So why did this young, inexperienced chemist get it right?

Dr. Gal thinks the answer might lie in the artistic passions of Pasteur’s youth. Even as a scientist, Pasteur remained closely connected to art. He taught classes on how chemistry could be used in fine art and attended salons. He even carried around a notebook, jotting down 1-4 ratings of artwork he visited.

And then Dr. Gal stumbled upon a letter Pasteur had written to his parents about a lithographic portrait he had made of a friend.

Lithography back then involved etching a drawing onto a limestone slab with wax or oil and acid, and pressing a white piece of paper on top of it. The resulting picture was transposed, like a mirror image of the drawing left on the slab.

In his letter, Pasteur wrote:

“I think I have not previously produced anything as well drawn and having as good a resemblance. All who have seen it find it striking. But I greatly fear one thing, that is, that on the paper the portrait will not be as good as on the stone; this is what always happens.”

Eureka. “Isn’t this the explanation of how he saw the handedness on the crystals — because he was sensitized to that as an artist?” Dr. Gal proposed.

. . .

We now know that many drugs contain molecules that exist in two chiral forms, and that the two forms can react differently in the body. The most tragic example occurred in the 1950s and ’60s, when doctors prescribed Thalidomide, a drug for morning sickness and other ailments, to pregnant women. The drug also contained a chiral molecule that caused disastrous side effects in many babies.