Category: Economics of Science

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

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

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

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

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

. . .

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

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

. . .

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

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

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

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

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

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

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

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

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

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

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

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

For the full commentary see:

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

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

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

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

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

Kealey’s book, praised above, is:

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

“Most Published Research Findings Are False”

(p. 10) How much of biomedical research is actually wrong? John Ioannidis, an epidemiologist and health-policy researcher at Stanford, was among the first to sound the alarm with a 2005 article in the journal PLOS Medicine. He showed that small sample sizes and bias in study design were chronic problems in the field and served to grossly overestimate positive results. His dramatic bottom line was that “most published research findings are false.”

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

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

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

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

For the full essay see:

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

(Note: bracketed year added.)

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

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

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

The 2005 paper by Ioannidis mentioned above is:

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

Policy Reform, Such as Smaller Research Teams, Needed for Faster Big Breakthroughs

(p. D3) Miracle vaccines. Videophones in our pockets. Reusable rockets. Our technological bounty and its related blur of scientific progress seem undeniable and unsurpassed. Yet analysts now report that the overall pace of real breakthroughs has fallen dramatically over the past almost three-quarters of a century.

This month in the journal Nature, the report’s researchers told how their study of millions of scientific papers and patents shows that investigators and inventors have made relatively few breakthroughs and innovations compared with the world’s growing mountain of science and technology research. The three analysts found a steady drop from 1945 through 2010 in disruptive finds as a share of the booming venture, suggesting that scientists today are more likely to push ahead incrementally than to make intellectual leaps.

“We should be in a golden age of new discoveries and innovations,” said Michael Park, an author of the paper and a doctoral candidate in entrepreneurship and strategic management at the University of Minnesota.

. . .

The new method looks at citations more deeply to separate everyday work from true breakthroughs more effectively. It tallies citations not only to the analyzed piece of research but to the previous studies it cites. It turns out that the previous work is cited far more often if the finding is routine rather than groundbreaking. The analytic method turns that difference into a new lens on the scientific enterprise.

The measure is called the CD index after its scale, which goes from consolidating to disrupting the body of existing knowledge.

Dr. Funk, who helped to devise the CD index, said the new study was so computationally intense that the team at times used supercomputers to crunch the millions of data sets. “It took a month or so,” he said. “This kind of thing wasn’t possible a decade ago. It’s just now coming within reach.”

The novel technique has aided other investigators, such as Dr. Wang. In 2019, he and his colleagues reported that small teams are more innovative than large ones. The finding was timely because science teams over the decades have shifted in makeup to ever-larger groups of collaborators.

In an interview, James A. Evans, a University of Chicago sociologist who was a co-author of that paper with Dr. Wang, called the new method elegant. “It came up with something important,” he said. Its application to science as a whole, he added, suggests not only a drop in the return on investment but a growing need for policy reform.

“We have extremely ordered science,” Dr. Evans said. “We bet with confidence on where we invest our money. But we’re not betting on fundamentally new things that have the potential to be disruptive. This paper suggests we need a little less order and a bit more chaos.”

For the full story see:

William J. Broad. “What Happened to All of Science’s Big Breakthroughs?” The New York Times (Tuesday, January 24, 2023 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the story has the date Jan. 17, 2023 [sic], and has the same title as the print version.)

For Nature paper mostly discussed in the passages quoted above is:

Park, Michael, Erin Leahey, and Russell J. Funk. “Papers and Patents Are Becoming Less Disruptive over Time.” Nature 613, no. 7942 (Jan. 2023): 138-44.

The paper on team size, and co-authored by Wang, 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.

Regulations Slow the Creation and Adoption of Healthcare Breakthroughs

CPR is “cardiopulmonary resuscitation.” ECPR is “extracorporeal CPR.” The ATTEST randomized double-blind clinical trial (RCT) provided dramatic evidence of the efficacy of ECPR. But the INCEPTION RCT seemed to provide equally strong evidence of a lack of efficacy. The key difference is the high level of experience and dedication of those implementing the ATTEST RCT, and the lack of experience, and likely lower dedication of those in the INCEPTION RCT. Dr. Demetris Yannopoulos has improved his techniques through trial and error, probably in some ways that he can articulate and in other ways that are harder to articulate. Gary Klein with his naturalistic decision-making research, writes that experience gives emergency workers a quick “recognition” of what needs to be done in different situations.

At what point in the development of a therapy do you perform the canonical RCT? In the case of Emil Freireich’s four drug chemo-cocktail for curing childhood leukemia, he continually improved the ingredients and doses of the cocktail. If an RCT had been performed too early in that process, the result would have been a lack of efficacy, and a therapy would have been abandoned that had the potential to be developed into a useful efficacious therapy. Ditto for Vince DeVita’s development of his chemo-cocktail for curing Hodgkin’s Lymphoma. Ditto also for the development of the drug that eventually proved efficacious in the For Blood and Money book, where Stanford cancer doctor and Pharmacyclics co-founder acquired and developed cancer therapy Imbruvica, but abandoned it after an RCT of it failed. But Miller was ousted by major Pharmacyclics stock-holder, and entrepreneurial non-scientist, Bob Duggan, who did not want to give up on Imbruvica. Duggan persevered, overseeing its further development, until a later RCT was performed that proved efficacy.

In an earlier entry, I documented a much simpler and cheaper CPR innovation that also promises to improve heart failure therapy, called “neuroprotective CPR” (NCPR). Which one, if either, of ECPR or NCPR should we endorse? Ideally, in a fully function medical marketplace, we could comfortably say: “let the market decide.” Entrepreneurial scientists and physicians could develop the therapies and see how many willing patients would be willing to pay for each. Maybe the more expensive ECPR therapy would initially only be bought by the better-off. But as Yannopoulos improves it, as he is already working to do, making it simpler and cheaper, it would eventually be appealing to a broader customers. In Openness, I claim that this is the common path of a great many breakthrough innovations in areas outside of medicine.

Notice that the ECPR was heavily funded by the Helmsley Trust, a private foundation. This is consistent with my claim that medical innovation benefits from a diversity of funding sources, especially of private funding sources that are more likely to fund a diversity of methods and to take chances with heterodox ideas, partly motivated by private funders’ greater mission-orientation due to having more ‘skin-in-the-game.’

Notice also that Yannopoulos’s implementation of ECPR was constrained by a scarcity of trained personnel. Yannopoulos could not act as a nimble entrepreneur because massive regulations limit nimble entrepreneurship in healthcare. This is especially try on labor market issues where massive labor market regulations pile on top of massive healthcare regulations. Breakthrough innovations are usually implemented by small nimble start-ups. To create Disneyland, Walt Disney created WED Enterprises, instead of try to created it with the large incumbent The Walt Disney Company. Jonathan Bush tried nimble labor market innovation in healthcare, but was stymied by regulations. So in the ECPR case, Yannopoulos had the beds to care for more cardiac arrest patients, but could not fill those rooms because of a lack of trained healthcare workers. He could not simply offer higher pay. He was part of a larger organization where he had limited decision-rights that reduced his nimble control. (On the importance of decision-rights, see Koch 2007.)

(p. 27) In reality, by the time a patient without a pulse arrives in the E.R., we know what the outcome is going to be. We continue CPR and shock the patient if we can. We insert a breathing tube and connect it to a ventilator. We inject medications: adrenaline, heart-rhythm drugs. But these treatments almost always fail.

. . .

Demetris Yannopoulos, an interventional cardiologist and professor at the University of Minnesota Medical School who created its Center for Resuscitation Medicine, refused to accept that this was the best doctors could do. In 2014, he began performing ECPR, a treatment that was starting to catch on in a few places, mostly in Asia and Europe. To his surprise, patients he didn’t expect to survive ended up doing well.  . . .

When a patient in cardiac arrest is placed on an extracorporeal membrane oxygenation (ECMO) machine, as Sauer was, the treatment is called ECPR. The type of ECMO intervention used in ECPR provides full life support, which means it does the work of both lungs and heart. (Another type of ECMO, used on Covid-19 patients, helps just with breathing.) ECMO evolved from the heart-lung machines that started being used during heart surgery in the 1950s.

. . .

ECPR by itself doesn’t actually cure anything. But by providing fresh blood flow to the brain and other organs, it lets the body rest and gives doctors time to fix the underlying problem, if it’s fixable.  . . .  After patients are hooked up to ECMO, angiograms of their hearts are typically performed to determine whether they have clogged arteries — as about 85 percent do. In Sauer’s case, Yannopoulos found a blockage in his largest heart vessel, the left anterior descending artery, also known as “the widow maker.” He inserted a stent to open it back up.

. . .

(p. 28) Several years after the program started, Yannopoulos, Bartos and their team conducted the first randomized, controlled trial of ECPR. The results were published in The Lancet in 2020 as the ARREST trial.  . . .

After enrolling just 30 patients, the ARREST trial was stopped early by an N.I.H. board because the patients who got ECPR did so much better than the control-group subjects who received standard resuscitation, and it would have been unethical to continue the study. After six months, 43 percent of the 14 patients who got ECPR were alive with good brain function, compared with zero in the control group.

. . .

The Helmsley Trust gave Yannopoulos grants totaling $19.4 million, which enabled him to add this “hub and spoke” mobile component to his program: The university hospital would be the hub, and a truck and some local hospitals would be the spokes. “It was a real big bet,” Panzirer told me.

To reach patients in areas that were more suburban and rural, Yannopoulos first had to team up with surrounding health systems. Competition is more often the norm among health systems, rather than collaboration, but he persuaded his chief executive, James Hereford, to gather his counterparts from other institutions. Eventually, they were willing to work together. But they had to sort out a lot more than simply agreeing to collaborate. How would insurers pay for what they were doing? Would the initial hospital get the money, or would the university hospital? Would malpractice coverage protect doctors outside their own institutions? What about transport?

Every question could be turned into a reason for hospital administrators and lawyers to say no.

. . .

(p. 29) The economics of ECPR are in line with those of other established lifesaving interventions, like dialysis and heart transplants. And if patients don’t survive, ECPR may perfuse their bodies with enough oxygen to keep their organs eligible for donation. The program in Minnesota costs about $3.2 million a year to operate, which is covered by its revenue. This doesn’t include the start-up funding from the Helmsley Trust, however, or the significant groundwork Yannopoulos laid before that — or his personal sacrifices. “When I started, I had hair and my beard was black,” says Yannopoulos, who is mostly bald and gray. For seven years, he was not paid for his ECPR work; some years, he was on call every day. Today, he still spends about 6,500 hours on call annually. “It’s the force of his will more than anything,” Hereford says when explaining why the program has succeeded.

. . .

Yannopoulos has invited physicians from all over to visit his program; afterward, he often hears from them that replicating his work at their home institutions — getting health and E.M.S. systems to collaborate, finding institutional support and start-up funding, coordinating 24/7 staffing — seems too daunting. For these reasons, Yannopoulos regards his ECPR program as “an administrative and political achievement, rather than a scientific or technological one.”

. . .

(p. 30) The trial, called INCEPTION, compared ECPR with standard care across 10 medical centers in the Netherlands. It was the first randomized, controlled trial to look at ECPR across multiple facilities, and unlike the ARREST trial, it found that ECPR resulted in similar survival as standard treatments.  . . .

Yet there are reasons to interpret the study as saying more about the real-world challenges of developing and implementing ECPR programs than it does about the treatment itself. In the INCEPTION trial, it took roughly a half-hour longer for patients to get on an ECMO machine once they arrived at the hospital than it did in the ARREST study. Of the patients who got ECPR, 12 percent were not successfully connected to the machines, compared with zero in ARREST. Several Dutch hospitals handled only a couple of ECPR cases a year, which means they hadn’t yet acquired the right skills. “I think they were destined for failure because of that rollout, with no experience up front,” Bartos says.

Experience matters profoundly: According to a 2022 paper based on data from the Extracorporeal Life Support Organization, an international nonprofit that Robert Bartlett founded, patients treated at centers that perform fewer than 10 ECPR procedures yearly have 64 percent lower odds of survival; for every 10-case increase, the odds go up 11 percent. (The Minnesota program treats about 150 every year.)

Not only does the procedure itself require mastery, but so, too, does the care in the I.C.U. afterward — an ineffable art as much as a precise science.

. . .

(p. 45) . . . it’s not much of a surprise to hear Yannopoulos ask, “What does INCEPTION have to do with what we’re doing?” His program was carefully developed, with deep expertise, over years, to achieve the best outcomes; INCEPTION studied what would happen if a lot of hospitals started doing ECPR tomorrow.

Engineering the ideal ECPR program can feel like a maddening calculus involving experience, availability and distance — all to beat time. To treat patients faster, maybe doctors should go directly to the scene. For more than a decade, doctors in France have been doing just that, performing ECPR on the streets of Paris, in Métro stations, even on the oak parquet floors of the Louvre. Early on, Lionel Lamhaut, the head of Paris’s ECMO team, was told that he was “a cowboy to try to do something outside the hospital.” But as he and his colleagues persisted, they “started a new way of thinking.”

. . .

. . . as much money as the Helmsley Trust has given, it is not enough to overcome some of the structural limitations in the American health care system. The organization funded a multimillion-dollar expansion of the cardiovascular I.C.U. at Yannopoulos’s hospital to add 12 more spacious rooms specifically designed to accommodate patients on ECMO. But on a weekend in January when I visited, the I.C.U. was closed to new ECPR patients: Not enough nurses were available to work, so four beds in the unit were kept empty.

Even as Yannopoulos and his team hit administrative roadblocks like these, they are still trying to redefine what is medically possible. Recently, a 74-year-old man collapsed on the streets of St. Paul and went into cardiac arrest. Forty-two minutes after the first 911 call, the man was already on ECMO and had regained his pulse. Yannopoulos was optimistic about the case, given how quickly ECMO was started, even though the patient had not been shocked with a defibrillator — which meant he technically fell outside the protocol and should not have received ECPR at all. (After a week in the I.C.U., the man died when his family decided to stop all treatment.)

The man’s heart was almost certainly in pulseless electrical activity (P.E.A.), which many experts think should not be treated with ECPR. Of the three published ECPR randomized, controlled trials, only one did not limit the intervention to people with shockable rhythms. That ambitious trial, in Prague, included patients whose hearts were in the same P.E.A. pattern as the St. Paul man’s. The study was stopped early when it appeared that ECPR wasn’t saving significantly more people than standard care was. These enigmatic cases that lack shockable rhythms are vexing: When the Prague data was reanalyzed without these patients, the findings were favorable for ECPR.

Yannopoulos is undeterred by the Prague results. “You have to decide what’s more important: your survival rate” — what is often used in studies and by institutions to justify support for a program — “or the number of patients you actually save.” Because its program is now well established, Yannopoulos’s team is starting to treat patients with less promising rhythms, even though that may drive down its overall survival rate.  . . .

Yannopoulos wonders if, in a decade or perhaps less, ECPR science will still require the same specially trained teams using the same high-tech equipment — at least before patients get to the hospital. Instead, he imagines small cannulas that will be easy to place in the patient’s neck and attached to compact, simple machines that provide some blood flow to the brain. In his vision, which he is currently working to realize, medics could be trained to start people on this, and then doctors could transition them to regular ECMO once they reach the hospital. If the brain is protected, the rest of the body can eventually recover.

. . .

“There is this idea that people in cardiac arrest, you cannot harm them,” Yannopoulos says. For some doctors, that means cycling relentlessly through chest compressions and medications, so they feel as if they did everything they could. For others, it means briefly going through the motions, so they feel as if they did something. And for still others, it has always seemed kindest to do nothing at all, to let their patients die peacefully. Because almost none of them lived — no matter what the doctors did. “But now we know what is possible,” Yannopoulos says. “So if you’re not achieving that, then you are harming them in a way, right?”

For the full story see:

Helen Ouyang. “Reinventing CPR.” The New York Times Magazine (Sunday, March 31, 2024): 22-31 & 45.

(Note: ellipses added.)

(Note: the online version of the story was updated June [sic] 19, 2024, and has the title “The Race to Reinvent CPR.”)

Some references relevant to my discussion at the start of this entry are:

Bush, Jonathan, and Stephen Baker. Where Does It Hurt?: An Entrepreneur’s Guide to Fixing Health Care. New York: Portfolio, 2014.

DeVita, Vincent T., and Elizabeth DeVita-Raeburn. The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable–and How We Can Get There. New York: Sarah Crichton Books, 2015.

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

Klein, Gary A. Seeing What Others Don’t: The Remarkable Ways We Gain Insights. Philadelphia, PA: PublicAffairs, 2013.

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

Klein, Gary A. Streetlights and Shadows: Searching for the Keys to Adaptive Decision Making. Cambridge, MA: The MIT Press, 2009.

Koch, Charles G. The Science of Success: How Market-Based Management Built the World’s Largest Private Company. Hoboken, NJ: Wiley & Sons, Inc., 2007.

Silberner, Joanne. “How a Plunger Improved CPR.” The New York Times (Tues., June 27, 2023): D5.

Taleb, Nassim Nicholas. Skin in the Game: Hidden Asymmetries in Daily Life. New York: Random House, 2018.

Vardi, Nathan. For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug. New York: W. W. Norton & Company, 2023.

Before Co-founding “Colossal” Private For-Profit Firm, George Church “Was Planning on Slogging Along at a Slow Pace” in Academia

Harvard Professor George Church chooses to pursue his bold dream of bringing wooly mammoths back to life through a private firm rather than through a nonprofit organization or an educational institution. Is that because nimble innovation is less constrained in a private for-profit firm?

(p. D3) A team of scientists and entrepreneurs announced on Monday that they have started a new company to genetically resurrect the woolly mammoth.

The company, named Colossal, aims to place thousands of these magnificent beasts back on the Siberian tundra, thousands of years after they went extinct.

“This is a major milestone for us,” said George Church, a biologist at Harvard Medical School, who for eight years has been leading a small team of moonlighting researchers developing the tools for reviving mammoths. “It’s going to make all the difference in the world.”

. . .

The idea behind Colossal first emerged into public view in 2013, when Dr. Church sketched it out in a talk at the National Geographic Society.

. . .

Russian ecologists have imported bison and other living species to a preserve in Siberia they’ve dubbed Pleistocene Park, in the hopes of turning the tundra back to grassland. Dr. Church argued that resurrected woolly mammoths would be able to do this more efficiently. The restored grassland would keep the soil from melting and eroding, he argued, and might even lock away heat-trapping carbon dioxide.

Dr. Church’s proposal attracted a lot of attention from the press but little funding beyond $100,000 from PayPal co-founder Peter Thiel.

. . .

“Frankly, I was planning on slogging along at a slow pace,” Dr. Church said. But in 2019, he was contacted by Ben Lamm, the founder of the Texas-based artificial intelligence company Hypergiant, who was intrigued by press reports of the de-extinction idea.

Mr. Lamm visited Dr. Church’s lab, and the two hit it off. “After about a day of being in the lab and spending a lot of time with George, we were pretty passionate on pursuing this,” Mr. Lamm said.

Mr. Lamm began setting up Colossal to support Dr. Church’s work, all the way from tinkering with DNA to eventually placing “a functional mammoth,” as Dr. Hysolli calls it, in the wild.

The company’s initial funding comes from investors ranging from Climate Capital Collective, an investment group that backs efforts to lower carbon emissions, to the Winklevoss twins, known for their battles over Facebook and investments in Bitcoin.

. . .

Heather Browning, a philosopher at the London School of Economics, said that whatever benefits mammoths might have to the tundra will need to be weighed against the possible suffering that they might experience in being brought into existence by scientists.

“You don’t have a mother for a species that — if they are anything like elephants — has extraordinarily strong mother-infant bonds that last for a very long time,” she said. “Once there is a little mammoth or two on the ground, who is making sure that they’re being looked after?”

And Colossal’s investors may have questions of their own: How will these mammoths make any money? Mr. Lamm predicted that the company would be able to spin off new forms of genetic engineering and reproductive technology.

“We are hopeful and confident that there will be technologies that come out of it that we can build individual business units out of,” Mr. Lamm said.

For the full story see:

Carl Zimmer. “MATTER; A Company Aims to Restock the Woolly Mammoth.” The New York Times (Tuesday, September 14, 2021 [sic]): D3.

(Note: ellipses added.)

(Note: the online version of the story was updated Sept. 30 [sic], 2021 [sic], and has the title “MATTER; A New Company With a Wild Mission: Bring Back the Woolly Mammoth.”)

“Heavily Subsidized Renewables” Mostly Add to Total Energy Consumed Instead of Replacing Fossil Fuels

(p. A17) Despite extravagant hype, the green-energy transition from fossil fuels isn’t happening. Achieving a meaningful shift with current policies is too costly. We need to change policy direction entirely.

. . .

Studies show that when countries add more renewable energy, it does little to replace coal, gas or oil. It simply adds to energy consumption. Recent research shows that for every six units of green energy, less than one unit displaces fossil-fuel energy. The Biden administration finds that while renewable energy sources worldwide will dramatically increase up to 2050, that won’t be enough even to begin replacing fossil fuels—oil, gas and coal will all keep increasing, too.

. . .

The current plan underpinning the green-energy transition mostly insists that pushing heavily subsidized renewables will magically make fossil fuels disappear. But such expectations are “misleading,” as a 2019 academic study concluded. During past additions of a new energy source, the researchers found, it has been “entirely unprecedented for these additions to cause a sustained decline in the use of established energy sources.”

What causes us to change our relative use of energy? One study investigated 14 shifts that happened over the past five centuries, such as when farmers went from plowing fields with animals to tractors powered by fossil fuels. Invariably, the new energy source would be better or cheaper.

. . .

The way to achieve an eventual transition is to improve green-energy alternatives. That means investing much more in research and development. Innovation is needed in wind and solar, as well as storage, nuclear energy, and other possible solutions. Bringing the costs of low-CO2₂energy sources below those of fossil fuels is the only way that green solutions can be implemented globally, and not merely by a few wealthy countries.

When politicians say the green transition is here, they are really asking voters to support throwing more good money after bad. We need to be smarter.

For the full commentary see:

Bjorn Lomborg. “The ‘Green Energy Transition’ That Wasn’t.” The Wall Street Journal (Tuesday, June 25, 2024): A17.

(Note: ellipses added.)

(Note: the online version of the commentary has the date June 24, 2024, and has the same title as the print version.)

The “recent research” mentioned above is:

Rather, Kashif Nesar, and Mantu Kumar Mahalik. “Investigating the Assumption of Perfect Displacement for Global Energy Transition: Panel Evidence from 73 Economies.” Clean Technologies and Environmental Policy (2023) https://doi.org/10.1007/s10098-023-02689-8.

The “2019 academic study” mentioned above is:

York, Richard, and Shannon Elizabeth Bell. “Energy Transitions or Additions?: Why a Transition from Fossil Fuels Requires More Than the Growth of Renewable Energy.” Energy Research & Social Science 51 (May 2019): 40-43.

The study of 14 shifts in type of energy that was mentioned above is:

Fouquet, Roger. “The Slow Search for Solutions: Lessons from Historical Energy Transitions by Sector and Service.” Energy Policy 38, no. 11 (Nov. 2010): 6586-96.

With Metformin Patent Expired, No Firm Has Incentive to Fund $50 Million Randomized Clinical Trial to Show It Aids Longevity

The article quoted below was published eight years ago. Dr. Barzilai and his team are still, even now, trying to raise the (probably higher) funds to conduct the metformin clinical trial. Firms have no incentive to conduct the clinical trial. Since the patent for metformin (originally issued for its efficacy against diabetes) expired in the year 2000, even if the clinical trial succeeded, no firm would be able to recover in revenue the $50 cost of conducting the clinical trial. Clinical trials are so hugely expensive largely due to the large and long Phase 3 component, intended to prove efficacy. That is why I salute Milton Friedman’s suggestion that a step in the right direction would be for the FDA to only mandate the smaller and quicker Phase 1 and Phase 2 components, mainly intended to prove safety. If the total cost of the clinical trial was much lower, it might be easier to find non-profit or academic funding. (It’s hard to raise $50 million on a GoFundMe page!)

The system is set up so that cheap (off-patent) drugs like metformin do not get tested, and so do not get FDA approval for off-label uses. So the system is set up to reduce the use of low cost, but possibly effective, medicines.

(p. D5) “Aging is by far the best predictor of whether people will develop a chronic disease like atherosclerotic heart disease, stroke, cancer, dementia or osteoarthritis,” Dr. James L. Kirkland, director of the Kogod Center on Aging at the Mayo Clinic, said in an interview. “Aging way outstrips all other risk factors.”

He and fellow researchers, who call themselves “geroscientists,” are hardly hucksters hawking magic elixirs to extend life. Rather, they are university scientists joined together by the American Federation for Aging Research to promote a new approach to healthier aging, which may — or may not — be accompanied by a longer life. They plan to test one or more substances that have already been studied in animals, and which show initial promise in people, in hopes of finding one that will keep more of us healthier longer.

As Dr. Kirkland wrote in . . ., “Aging: The Longevity Dividend”: “By targeting fundamental aging processes, it may be possible to delay, prevent, alleviate or treat the major age-related chronic disorders as a group instead of one at a time.”

. . .

The team, which includes Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine in The Bronx, and Steven N. Austad, who heads the biology department at the University of Alabama at Birmingham, plans to study one promising compound, a generic drug called metformin already widely used in people with Type 2 diabetes. They will test the drug in a placebo-controlled trial involving 3,000 elderly people to see if it will delay the development or progression of a variety of age-related ailments, including heart disease, cancer and dementia. Their job now is to raise the $50 million or so needed to conduct the study for the five years they expect it will take to determine whether the concept has merit.

. . .

Several studies have . . . found that individuals with exceptional longevity experience a compression of morbidity and spend a smaller percentage of their life being ill, Dr. Barzilai and his colleague Dr. Sofiya Milman wrote in the “Aging” book.

For the full commentary see:

Jane E. Brody. “Pursuing the Dream of Healthy Aging.” The New York Times (Tuesday, February 2, 2016 [sic]): D5.

(Note: ellipses added.)

(Note: the online version of the commentary has the date February 1, 2016 [sic], and has the title “Finding a Drug for Healthy Aging.”)

Dr. Kirkland’s co-edited book mentioned above is:

Olshansky, S. Jay, George M. Martin, and James L. Kirkland, eds. Aging: The Longevity Dividend, A Subject Collection from Cold Spring Harbor Perspectives in Medicine. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2015.

One study that documents that those who live 107 or more years do not have more years of illness and morbidity (the “compression of morbidity hypothesis”) is:

Sebastiani, Paola, and Thomas T. Perls. “The Genetics of Extreme Longevity: Lessons from the New England Centenarian Study.” Frontiers in Genetics 3 (Nov. 30, 2012).

“A Major Environmental Group” Will Fund Geoengineering Research

(p. A18) The Environmental Defense Fund will finance research into technologies that could artificially cool the planet, an idea that until recently was viewed as radical but is quickly gaining attention as global temperatures rise at alarming rates.

The group hopes to start issuing grants this fall, said Lisa Dilling, associate chief scientist at E.D.F., who is running the project. She said research would focus on estimating the likely effects in different parts of the world if governments were to deploy artificial cooling technologies.

. . .

The Environmental Defense Fund has previously expressed skepticism about techniques like these. But Dr. Dilling says the discussion about ways to cool the planet isn’t going away, regardless of opposition. “This is something that I don’t think we can just ignore,” she said.

The group will fund what is sometimes called solar radiation modification, or solar geoengineering, which involves reflecting more of the sun’s energy back into space. Possible techniques involve injecting aerosols into the stratosphere, or brightening clouds to make them more reflective.

. . .

That a major environmental group like the Environmental Defense Fund is investing in solar geoengineering research sends a powerful message, said Larry Birenbaum, a partner at the LAD Climate Fund, one of the groups funding the research. He said his group had been urging environmentalists for years to pay attention to solar geoengineering.

“We’re not going to convince everyone about the necessity for research,” said Mr. Birenbaum, a former senior vice president at Cisco Systems. “The climate community in general needs to be convinced, because this is on the fringe now, and it deserves not to be.”

For the full story see:

Christopher Flavelle. “Experiments to Artificially Cool the Earth Are Getting a Major Backer.” The New York Times (Tuesday, June 11, 2024): A18.

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

(Note: the online version of the story has the date June 10, 2024, and has the title “Environmental Group to Study Effects of Artificially Cooling Earth.”)

“Serendipitous” Discoveries Related to Two “Odd-Looking” Animals Was Source of Weight-Loss Drugs

(p. A1) The blockbuster diabetes drugs that have revolutionized obesity treatment seem to have come out of nowhere, turning the diet industry upside down in just the past year. But they didn’t arrive suddenly. They are the unlikely result of two separate bodies of science that date back decades and began with the study of (p. A2) two unsightly creatures: a carnivorous fish and a poisonous lizard.

In 1980, researchers at Massachusetts General Hospital wanted to use new technology to find the gene that encodes a hormone called glucagon. The team decided to study Anglerfish, which have special organs that make the hormone, simplifying the task of gathering samples of pure tissue.

. . .

After plucking out organs the size of Lima beans with scalpels, they dropped them into liquid nitrogen and drove back to Boston. Then they determined the genetic sequence of glucagon, which is how they learned that the same gene encodes related hormones known as peptides. One of them was a key discovery that would soon be found in humans, too.

It was called glucagon-like peptide-1 and its nickname was GLP-1.

After they found GLP-1, others would determine its significance. Scientists in Massachusetts and Europe learned that it encourages insulin release and lowers blood sugar. That held out hope that it could help treat diabetes. Later they discovered that GLP-1 makes people feel fuller faster and slows down emptying of food from the stomach.

. . .

The key to the first drug would come from a serendipitous discovery inside another odd-looking animal.

Around the time Goodman was cutting open fish, Jean-Pierre Raufman was studying insect and animal venoms to see if they stimulated digestive enzymes in mammals.

“We got a tremendous response from Gila monster venom,” he recalled.

It was a small discovery that could have been forgotten, but for a lucky break nearly a decade later when Raufman gave a lecture on that work at the Bronx Veterans Administration. John Eng, an expert in identifying peptides, was intrigued. The pair had collaborated on unrelated work a few years before. Eng proposed they study Gila monsters.

. . .

Eng isolated a small peptide that he called Exendin-4, which they found was similar to human GLP-1.

Eng then tested his new peptide on diabetic mice and found something intriguing: It not only reduced blood glucose, it did so for hours. If the same effect were to be observed in humans, it could be the key to turning GLP-1 into a meaningful advance in diabetes treatment, not just a seasickness simulator in an IV bag.

Jens Juul Holst, a pioneering GLP-1 researcher, remembers standing in an exhibit hall at a European conference next to Eng. The two had put up posters that displayed their work, hoping top researchers would stop by to discuss it. But other scientists were skeptical that anything derived from a lizard would work in humans.

“He was extremely frustrated,” recalled Holst. “Nobody was interested in his work. None of the important people. It was too strange for people to accept.”

After three years, tens of thousands of dollars in patent-related fees and thousands of miles traveled, Eng found himself standing with his poster in San Francisco. This time, he caught the attention of Andrew Young, an executive from a small pharmaceutical company named Amylin.

“I saw the results in the mice and realized this could be druggable,” Young said.

When an Eli Lilly executive leaned over his shoulder to look at Eng’s work, Young worried he might miss his chance. Not long after, Amylin licensed the patent.

They worked to develop Exendin-4 into a drug by synthesizing the Gila monster peptide. They weren’t sure what would happen in humans. “We couldn’t predict weight loss or weight gain with these drugs,” recalled Young. “They enhance insulin secretion. Usually that increases body weight.” But the effect on slowing the stomach’s processing of food was more pronounced and Young’s team found as they tested their new drug that it caused weight loss.

To get a better understanding of Exendin-4, Young consulted with Mark Seward, a dentist raising more than 100 Gila monsters in his Colorado Springs, Colo., basement. The lizard enthusiast’s task was to feed them and draw blood. One took exception to the needle in its tail, slipped its restraint and snapped its teeth on Seward’s palm—the only time he’s been bitten in the decades he’s raised the animals. “It’s like a wasp sting,” he said, “but much worse.”

Nine years after the chance San Francisco meeting between Eng and Young, the Food and Drug Administration approved the first GLP-1-based treatment in 2005.

The twice-daily injection remained in the bloodstream for hours, helping patients manage Type 2 diabetes. Eng would be paid royalties as high as $6.7 million per year for the drug, . . .

For the full story, see:

Rolfe Winkler and Ben Cohen. “Two Monsters Spawned Huge Drugs.” The Wall Street Journal (Friday, June 24, 2023): A1-A2.

(Note: ellipsis added.)

(Note: the online version of the story has the date June 23, 2023, and has the title “Monster Diet Drugs Like Ozempic Started With Actual Monsters.” The sentence about “a serendipitous discovery” appears in the online, but not the print, version of the article. The passages quoted above also include several other sentences that appear in the more extensive online version, but not in the print version.)

Temple Grandin Admires Elon Musk and Long Knew He Was on the Autism Spectrum

Professor Temple Grandin identifies as autistic and has written on what we can learn from the cognitively diverse. In the passages quoted below, she refers to the May 2021 Saturday Night Live hosted by Elon Musk in which he said he had Asperger’s syndrome.

(p. C7) I have always admired Elon Musk’s engineering of rockets and cars. I loved his cool space suits and how he made a rocket booster land upright. My must-read book is Walter Isaacson’s “Elon Musk.” Previously I had read Ashlee Vance’s book about Mr. Musk. It still has Post-it Notes stuck on it: I marked the pages that made me sure he was on the autism spectrum. I had to keep it to myself until he made his announcement on “Saturday Night Live.”

For the full review, see:

Temple Grandin. “12 Months of Reading: Temple Grandin.” The Wall Street Journal (Saturday, December 9, 2023): C7.

(Note: ellipsis added.)

(Note: the online version of the review has the date December 8, 2023, and has the title “Who Read What in 2023: Leaders in Business, Science and Technology: Temple Grandin.”)

The Elon Musk books Temple Grandin praises are:

Isaacson, Walter. Elon Musk. New York: Simon & Schuster, 2023.

Vance, Ashlee. Elon Musk: Tesla, SpaceX, and the Quest for a Fantastic Future. New York: Ecco, 2015.

Global Warming Can Allow a “Sudden Efflorescence” of Adaptation from Dormant “Sleeping Beauties”

Above the title of the book review quoted below, the Wall Street Journal printed a few lines from a poem by Baudelaire:

Many a jewel of untold worth
Lies slumbering at the core of Earth
In darkness and oblivion drowned . . .
–Charles Baudelaire, “Le Guignon”

(p. C12) In his new book, Mr. [Andreas] Wagner, a professor at the Department of Evolutionary Biology and Environmental Studies at the University of Zurich, showcases biological “sleeping beauties”: animals, plants, even bacteria that for generations plugged along with modest evolutionary success, only to later flourish spectacularly. “Sleeping Beauties: The Mystery of Dormant Innovations in Nature and Culture” explains how evolutionary adaptations sometimes go from dormancy to full flowering, while also suggesting that an analogous process applies to human innovations, including science, technology and the arts.

. . .

First we need to recall that not every biological trait an organism possesses is optimal for its current environment. The swim bladder, for example, evolved in fish as an aid to adjusting buoyancy, only later becoming the basis for lungs when their descendants became terrestrial. And the human appendix currently appears to be more an evolutionary liability than an asset, although it may well have conveyed immunologic benefits in the past—and could even prove adaptive in the future. Certain traits may develop that are not immediately adaptive, in the sense of contributing directly to the reproductive success of the genes responsible for the trait and of the individuals carrying them.

If an organism develops a characteristic maladapted to its environment, it and the genes responsible for the trait are selected away into oblivion. But if the novelty is not particularly harmful, or even somewhat helpful, the trait may simply hang around through the generations—until a descendant organism finds a welcoming environmental niche.

The natural world is filled with solutions awaiting a problem.  . . .  But when environments change (and they always do), a wonderful and lively explosion can ensue.

Mr. Wagner refers to this sudden efflorescence as “adaptive radiation”—“only with a key innovation,” he writes, “can a species exploit existing opportunities, such as a warmer climate, a new source of food, or a superior form of shelter. In this view, any one adaptive radiation has to wait, possibly for a long time, until the right innovation arises. And the need to wait holds evolution back.”

In regard to evolutionary developments that at first seem to bear no fruit, Mr. Wagner could have quoted from Thomas Gray’s “Elegy Written in a Country Churchyard”:

Full many a gem of purest ray serene,
The dark unfathom’d caves of ocean bear:
Full many a flow’r is born to blush unseen,
And waste its sweetness on the desert air.

In the world of human creativity, “full many” a terrific creation has been neglected or ignored in its time.

For the full review, see:

David P. Barash. “In Praise of Late Bloomers.” The Wall Street Journal (Saturday, April 29, 2023): C12.

(Note: ellipses, and bracketed name, added, except for first one at the end of quoted passage from Baudelaire.)

(Note: the online version of the review has the date April 28, 2023, and has the title “‘Sleeping Beauties’ Review: Nature’s Late Bloomers.”)

The book under review is:

Wagner, Andreas. Sleeping Beauties: The Mystery of Dormant Innovations in Nature and Culture. London: Oneworld Publications, 2023.