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The Covid-19 Vaccine and Transgender Sports: A (Plausible?) Trumpian Connection (guest post from the spouse)

On February 5 President Trump signed an executive order barring transgender student athletes from playing in girls’ sports. On March 19, the National Institutes of Health told grant seekers across the country to remove any reference to mRNA vaccine technology from their grant applications. What do these two things have to do with each other?

Maybe nothing. However, it is also possible that the Trump administration is trying to kill two birds with one stone and is using the University of Pennsylvania as its target. On the same day that the NIH promulgated its directive to remove mRNA vaccine technology from grant applications, the Trump administration “paused” $175 million in grant funding to the University of Pennsylvania. The grants are being “paused,” the administration says, over Penn’s failure to exclude the transgender student Lia Thomas from the women’s swim team. Is it a coincidence that the most notable research team in mRNA vaccine technology, Katalin Karikó and Drew Weissman, work at the University of Pennsylvania Medical School? Oh, and by the way, in 2023 they won the Nobel Prize after their work led to saving an estimated 3 million lives from the scourges of the Covid-19 epidemic.

Whatever you may think about transgender women participating in women’s sports, it’s a very bad precedent that such an executive order pre-empted cases that were before the courts (Penn swimmers are suing the university), and it’s equally bad that Penn is being punished for a “failure” that is long past (Lia Thomas has graduated). But by targeting Penn, they are also targeting a Nobel Prize-winning team of scientists who are working on one of the most promising technologies currently available for treating dangerous viruses and cancer. One only hopes that those proposed $175 million cuts do not affect their research effort (they are heavily funded by NIH), but that remains to be seen.

Continuing my effort to explain the devastation being wreaked on American science, here is another effort to describe the incremental steps that led up to the Covid-19 vaccine and that Nobel Prize.

As before: some basic science information is worthwhile.

1) Basic molecular biology: DNA, the famous double helix, unwinds and provides a template for RNA. This is called “transcription.” RNA, which comes in both double and single strands, then codes for proteins. This is called “translation.” Proteins make up just about everything in the body…muscles, bones, nerves, everything.

2) Basic immunology: When a virus invades the human body, the immune system recognizes it, and, if we’re lucky, mounts a response to destroy it. How does it “recognize” it? Molecules (called Toll receptors) on or within immune system cells match up with certain age-old molecular patterns on pathogens. When those receptors meet their match, the cells go into action by producing antibodies and/or other components of the immune response.

3) Basic vaccine biology: The protection afforded by vaccines has been known since 1796 when Edward Jenner realized that small doses of smallpox protected people from getting the full-blown symptoms of the disease. It took another hundred years (1890) before the concept of antibodies was promulgated and another 70 years after that (1958) before the structure and function of antibodies were known. And many years after that before the understanding of the immune cascade that produces them in the first place. Understanding how vaccines work to create antibody protection has been the focus of a massive research effort ever since. The National Institute of Allergy and Infectious Diseases provides about $6.5 billion annually to support that research.

4) How are these things related? That’s what took some time to discover.

That DNA had something to do with heredity was discovered in the 19th century, but its structure was not known until 1953. This discovery is famously described in the book by James Watson, The Double Helix. Watson, Francis Crick, and their male collaborator (Maurice Wilkins), but not their female collaborator (Rosalind Franklin), were awarded the Nobel Prize in 1962. Not surprisingly, then, the 1950’s and 60’s saw an explosion of research in DNA technology leading to an understanding of protein biosynthesis as described above.

In the meantime, work on the immune system progressed apace. While it was clear from research going back 100 years that certain molecules were able to stimulate an immune reaction, the mechanism by which this occurred was largely unknown until Toll receptors were discovered in 1985. They were discovered in embryos of Drosophila, i.e., fruit flies (another Nobel Prize for the team), but their role as the triggers of immune system function did not come for another ten years. Research on these basic elements of immune system activation flourished, and by the early 2000’s, nine different Toll-like receptors had been identified, some of which recognize RNA.

The plot thickens.

So. What if you could engineer a specific RNA to enter an immune cell, translate a small portion of an ugly virus…say, the “spike” surface protein of the Covid virus…then have that surface protein expressed by a non-viral cell? Since the surface protein by itself is harmless without its viral host, such production would not constitute a full-blown viral infection. The RNA would, of course, need to be modified so that it translated the protein but didn’t cause an overwhelming inflammatory response via those pesky Toll receptors. This necessary modification was the genius of Karisó and Weissman at Penn. The modified RNA would then stimulate intracellular Toll receptors to produce a more modest immune response. Would the immune system simultaneously recognize the surface protein and the modest Toll receptor response and mount a reaction that included the production of antibodies against the surface protein? Would that be the equivalent to a vaccine against Covid-19? And the answer is…well, yes. But how to get that RNA into the cell in the first place?

Another discovery, beginning in the 1960’s, showed that tiny lipid (fatty) droplets (nanoparticles) could encapsulate molecules like RNA and “squeeze” it into cells. Hence, they provided a delivery system for the RNA. And this observer has not a single idea about how one gears up the production of this entire apparatus to enable the vaccination of millions of humans. Enter the technology of the pharmaceutical giants….way beyond the scope of this humble essay.

In short, several strands of research over many decades had to come together in order to beat the Covid virus. But questions remain. Can we use this technology to fight cancer? Autoimmune diseases? As-yet-unknown pathogens? Well, we won’t know if the Trump administration bans funding for anything smacking of the pernicious “mRNA technology.” Call your Congress person…NOW.

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First Sentences

“For most of Richard Nixon’s tenure as president, he had an insurance policy against impeachment and removal from office. Its name was Spiro Agnew.” Jeffrey Toobin, The Pardon: The Politics of Presidential Mercy.

“All children mythologize their birth.” Diane Setterfield, The Thirteenth Tale.

“The call to adventure came in libraries, in faculty offices, at campus football games.” Elyse Graham, Book and Dagger: How Scholars and Librarians Became the Unlikely Spies of World War II.

“It’s a Saturday morning, and I’m midway through my shift at the Winter Park Public Library when I see it.” Kristin Harmel, The Book of Lost Names.

“Two things happened the year I turned eleven: my father died and I became friends with my first professional chef, a guy named Jacques. Eric Ripert, 32 Yolks: From My Mother’s Table to Working the Line.

“The staff meeting of the Metropolitan Museum’s Department of Egyptian Art was supposed to start at ten, which meant associate curator Charlotte Cross arrived at nine to prepare her colleagues for battle.” Fiona Davis, The Stolen Queen.

“If something begins when it acquires a name we can date the beginnings of fascism precisely.” Robert O. Paxton, The Anatomy of Fascism.

“You must leave as few clues as possible.” Richard Osman, We Solve Murders.

“Noon, 8 September 2021. Central Paris, Île de ka Cité, under a heavy police guard. For the first time, several hundred of us walk through the security gates which we’ll pass through every day for a year.” Emmanuel Carrère, V13: Chronicle of a Trial (Translated from the French by John Lambert).

“Secretary of War Edwin Stanton learned over the bedside of his good friend, Abraham Lincoln, and, tears spilling down his cheeks, spoke the memorable phrase: now he belongs to the angels—or the ages.” Brenda Wineapple, The Impeachers: The Trial of Andrew Johnson and the Dream of a Just Nation.

“On a hot afternoon in May 2016, five miles outside the young petro-city of Fort McMurry Alberta, a small wildfire flickered and ventilated, rapidly expanding its territory through a mixed forest that hadn’t seen fire in decades.” John Vaillant, Fire Weather: On the Front Line of a Burning World

“On July 28, 1915, Rear Admiral Willaim B. Caperton stood on the quarterdeck of the USS Washington with a pair of binoculars at his eyes and several questions running through his head.” Sean Mirski, We May Dominate the World: Ambition, Anxiety, and Rise of the American Colossus.

“When Mac was three years old and Anya was five, they watched their mother get arrested for a seatbelt violation.” Alexandra Natapoff, Punishment without Crime: How our Massive Misdemeanor System Traps the Innocent and Makes America More Unequal.

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Snippets

I watch a lot of athletics on TV, perhaps too much. This viewing includes women sports, but I am planning to give up watching women’s college basketball, volleyball, and softball. They are too dominated by transgender women to be enjoyable and safe. Or at least that is the impression I get from watching too much Fox News and listening to too many of our politicians.

We know that many must study little if Shelley is right when he said, “The more we study the more we discover our ignorance.”

With DOGE ripping apart the country, I have mentally started calling our president Donlon Trusk.

A wise person said, “It seems unreasonable, but the head never begins to swell until the mind stops growing.”

A social media post has said that the Russians recruited Donald Trump decades ago. Trump may merely be a fanboy of Vladimir Putin; however, many of Trump’s actions, including the destruction of America’s standing in the world, could come from a Putin playbook. There is more plausibility in the conspiracy theory that Trump is a Russian asset than many others that take root. Instead of a Manchurian candidate, do we have a Siberian president?

“I don’t lie. I improve on life.” (Perhaps) Josephine Baker.

I asked Murphy what he did for St. Patrick’s Day. He said, “Nothing. St. Pat’s is a day for amateurs.”

Qatar is often mentioned on TV, but it is pronounced in different ways. What is the correct way to say it?

My friendly boss with Irish roots had moved to the suburbs. He invited us to a wine tasting at his new parish church. After it ended, we retired to his new home across the street. We were joined by other Irish Americans who had been at the winetasting. As is usual when you put alcohol and Irish together, singing begins. An Irish Lullaby. Danny Boy. It was getting late. We were looking to get out of there since it was long drive home. We were about to stand up when a guitar appeared in the hands of a thin man. He looked around until the now raucous group got quiet. He started to sing. I have little familiarity with the genre, but it was an Irish protest song. He sang beautifully. If you weren’t crying by the end, you should have been.

I occasionally play Spelling Bee, an online game from the New York Times. You are to make words of at least four letters from seven letters with six arrayed in a circle around a seventh letter. Each word must contain that central letter. The game somewhere has an official word list, which I have never seen, but sometimes an entry that I know is a valid word, often a scientific or technical term, is rejected. However, on occasion I spot a word that I know does not exist, but I believe it should. For example, pignic: eating too much on the lawn.

Even though the administration is trying to tear down universities in the name of fighting antisemitism, it occurs to me that one of the flaws of the current administration is that it does not have enough Jewish people.

“He who blesses his neighbor with a loud voice, rising early in the morning, will be counted as cursing.” Proverbs.

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Snippets

I often think that I get those quotidian 50/50 choices wrong more than half the time. When I try to insert the USB cable, or the polarized plug, or pull on the up/down shade cord, push or pull the door, or similar everyday tasks, I seem to get it wrong far more often than I get it right. I keep meaning to keep track for a week to see if my perception is correct, but I have so far failed to perform this crucial experiment.

“I am always doing that which I cannot do, in order that I may learn how to do it.” Picasso.

There is much talk that Trump is destroying democracy, but as pointed out in Myth America: Historians Take On the Biggest Legends and Lies About Our Past. (2022) by Kevin M. Kruse and Julian E. Zelizer,“Majoritarian democracy may not sound like something so unusual for an American president to embrace, but the conservative movement had treated it with suspicion for decades.” In the 1960s, conservatives said again and again that United States is a republic, not a democracy. However, Akhil Reed Amar in his essay “Founding Myths” in Kruse and Zelizer’s book maintains that at this country’s founding many Americans treated “republic” and “democracy” as broadly the same.

Often when Trump starts rambling, I think of the statement by Fran Lebowitz: “Generally speaking, it is inhumane to detain a fleeting insight.”

“Neurosis seems to be a human privilege.” Freud.

I am now so old that I regularly watch “Wheel of Fortune” and some non-sports shows on CBS.

A wise person said: “Alas! It is man’s fate to keep on growing older long after he is old enough.”

“Life should consist in at least fifty per cent pure waste of time, and the rest in doing what you please.” Isabel Patterson.

“It is not true that life is one damn thing after another—it’s one damn thing over and over.” Edna St Vincent Millay.

“The biggest problem people have is leisure. Anybody can handle a jam-packed day.” Peg Bracken.

I have finally learned that a good listener is generally thinking about something else.

I have also learned that bores are people who would rather talk about themselves when I’d much rather talk about me.

I believe in being a gentleman if Oliver Herford is right when he said, “A gentleman is one who never hurts anyone’s feelings unintentionally.”

I believe in being on time. However: “The trouble with being punctual is that there’s nobody there to appreciate it.” Harold Rome.

I believe in love. “Love is a wonderful thing and highly desirable in marriage.” Rupert Hughes.

However: “I think unconditional love is what a mother feels for her baby, and not what you should feel for yourself.” Helen Gurley Brown.

“Life is a flame that is always burning itself out, but it catches fire again every time a child is born.” George Bernard Shaw.

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And Now for Something Completely Small (From the Spouse)

For as long as I can remember, I’ve loved miniature things. Well, we all love puppies and kittens and even human babies. But I loved miniature things, like dollhouses and the things that were inside them. Now. When I was a child in the 1950’s, a dollhouse from Sears and Roebuck was a somewhat boring affair: a metal box with a slanting roof, open on one side to reveal four cubes representing four nondescript rooms (where was the bathroom?). Still. It was small, and if you could find them in Woolworth’s and your mom would let you splurge a little, tiny pieces of plastic furniture could be housed inside. I thought that was pretty satisfying until I was 9 or so.

It was around that time that I became aware of the Colleen Moore Dollhouse at the Chicago Museum of Science and Industry. No mere house, this. It was a mansion of a million rooms (or so it seemed), each completely furnished down to the teeny rose in a teeny vase on a delicately carved mahogany table next to a velvet-covered settee carefully placed on a tiny Persian carpet. And it had electric lighting! Electrified chandeliers, electrified wall sconces. It was a revelation.

As I gawked at this magnificence, though, the pitiful contrast to my Sears and Roebuck box became far too apparent. Knowing that something so utterly amazing existed whose elegance and detail could never be duplicated (at least, not by me) quashed my interest in dollhouses for many years thereafter.

It was a bit later in life that I marveled at the historically accurate rendering of tiny rooms at the Chicago Art Institute. Conceived by Mrs. James Ward Thorne in the mid-twentieth century, the rooms were (“painstakingly” goes without saying) constructed on a scale of one inch to one foot, and there are 68 of them! It was overwhelming to the likes of me, and similarly discouraging. This was a life’s work – and an expensive one. It would take a highly dedicated Mrs. Thorne’s full-time efforts and considerable fortune to even think of duplicating a single room. Sigh.

I most certainly should have given up this interest in miniatures. But no. At Gainesville (Florida) High School I chaired the decorations committee for the senior prom. They could not have picked a more inept leader. Being a complete dufus, I envisioned an entrance to the dance floor (the gym) that would replicate – in miniature — the Gainesville main street at the turn of the century. Low-rise buildings, gas lights, cobble-stone streets. It was a complete and utter disaster! Neither I nor anyone on my committee had a clue on how even to begin. I have mostly repressed the whole affair, but I think somebody’s mother bailed me out by providing crepe paper streamers and Kleenex roses – like any sensible prom decorating committee should have done.

But I never really gave up being enamored of small things. Even my scientific career focused on things microscopic. Nothing gave more satisfaction than to examine through a microscope cells stained to show the delicate intricacies of their inner workings.

And in the meantime, I started to collect miniature tea sets. Cheap enough and still satisfyingly small. I learned that there are small tea sets (suitable for tea time with a teddy bear), smaller tea sets (not suitable for anything, really), and teensy, tiny tea sets (designed to please people like me who have a miniature fetish and a limited budget). The smallest I own came from a gift shop at The Greenbrier. The tray upon which the tea pot, sugar, creamer and two cups in saucers sits is no more than three centimeters in diameter. I love it. All of my tiniest treasures are now displayed in a shadow box that is ill-lit. No one really notices it, but I do, and when I do, it surprises and pleases.

Not knowing much about the military nor coming from a military family, I was never as intrigued by toy soldiers, but a friend, James Hillestad, has a most extraordinary collection of toy soldiers at the Toy Soldier Museum in Cresco, PA. Here are 3,000 square feet of full-scale models with 70 authentic military uniforms. You can see the battle at Vicksburg, parade scenes of Scottish bagpipers, the military review that attended Queen Victoria on a visit to India, etc. etc. In short, hundreds of toy soldiers are on breath-taking display. Definitely worth a trip to the Poconos or go to www.the-toy-soldier.com.

Well, okay, so when I retired, I decided to give my full-time effort to building a doll house. I bought a reasonably sized, reasonably priced kit to produce a Victorian house with four rooms (one is a bathroom!) and a front porch. I put wallpaper on its walls and carpets on its floors. The bathroom has “tiles.” The outside is painted dark green with white trim. It’s furnished of course, complete with a teeny, tiny copy of Scientific American on the living room coffee table. There’s a chandelier in the dining room, but it’s not electrified, and it keeps falling down. There’s a tray of wine and fruit available to guests. I decorate the outside for Christmas with battery-powered fairy lights. I love it. And…I have gotten that Moore/Thorne impulse out of my system.

I think of this topic because I recently saw what must be one of the most amazing miniaturization projects ever! The Ringling Circus Museum in Sarasota, Florida, houses a 3,800 square foot model of a circus conceived and built by one Howard C. Tibbals. It comprises (in small part) The Big Top (with 7,000 folding chairs and five rings), the Midway complete with side shows, a multitude of train cars that carry the 500 hand-carved elephants, tigers, and horses. Horses! Hundreds of horses both for work and for performing. There are clowns putting on make-up, the cooking tent and mess tent with maybe 500 people inside, each with his own tiny plate of food, a patrons’ parking lot with old-timey model cars, a wardrobe tent with tiny sequined circus costumes pouring out of tiny circus trunks. They say there are more than 42,000 individual pieces, not including railroad ties and tent poles. A separate exhibit shows the parade pageantry of the Big Top with hundreds of elephants, acrobats, and costumed beauties. Go to the Internet and put in Howard Bros. Circus. You’ll see; it is miraculous.

So, you see, there are more people than you might think who are driven to a lifetime of miniaturization. Bless ‘em! 

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The Ethical Federal Prosecutor

Santa Claus, an honest lawyer, and a disgusting, dirty, smelly drunk are on the sidewalk when they each see a leather case on the sidewalk. They rush to it and get there simultaneously. It has no lock, and after a few words, they agree to open it. The case is packed with crisp, wrapped $100 bills. The look at each other, and one asks, “What should we do it with it?” Santa Claus says, “I should get it. I will use it to get even more toys for underprivileged children.” The lawyer responds, “No. I will take it and find its rightful owner for this still belongs to someone. I will go to the police and the courts. I know how to advertise for lost property. I will work hard to return it.” The drunk slurs, “Just give it to me. No one will be happier. I will use the money to stay drunk for the rest of my days and never again have to bother others asking for cash.” Who gets the money? Of course, it is the drunk because Santa Claus and the honest lawyer are mythical creatures.

That joke fits in with the many preconceptions that lawyers are without ethics, but in fact attorneys are in a profession that has some stringent ethical codes. Recent news has highlighted that.

Just last week the Supreme Court decided a death penalty case from Oklahoma. The Oklahoma Attorney General told the Court that the defendant had, in fact, been given an unfair trial because the Oklahoma trial prosecutors had not lived up to their legal and ethical duties. “Confessions of error” are highly unusual, and the Oklahoma AG took much abuse for his ethical stand. (The Supreme Court, to the surprise of many, did actually reverse the conviction.)

More familiar is the situation of New York City Mayor Eric Adams. Last fall Adams was charged by the federal government with various corrupt acts. The case was proceeding to trial when the new Justice Department dismissed the charges indicating that Adams could more effectively carry out Trump’s immigration mandates if Adams did not have to stand trial. They dismissed the case “without prejudice,” meaning that they could bring back the charges later if they so chose. This, of course, “incentivized” Adams to do the bidding of the Trump administration. The apparent quid pro quo looked unethical to many. At least eight Justice Department attorneys did what they thought was ethically demanded of them: They resigned.

More recently, Ed Martin, the acting U.S. Attorney for the District of Columbia, demoted seven or eight experienced Assistant U.S. Attorneys who were involved in January 6 prosecutions. Martin defended the demotions by saying that each U.S. attorney “must assess the needs of the office to achieve the goals set forth by the President and the Attorney General.” Martin cited nothing to indicate that the attorneys had or were performing poorly. Instead, the demotions clearly seemed a retribution for actions taken when Trump was not president. The goal seemed to humiliate the prosecutors for performing their jobs ethically. They are now restricted to handling matters normally given to fledgling attorneys starting out in the office. It seems that the acting U.S. attorney hopes that such a demotion will cause them to quit. This action has raised questions about Ed Martin’s ethics.

These actions highlight the unusual role that attorneys and especially prosecutors have in our federal government. More than a few “distinguished” conservative commentators have said that the Attorney General and U.S. Attorneys must follow the president’s directions “because they work for the president.” That’s just not true. Neither an Attorney General nor other federal officials work for the president. He does not pay them, and no one in the government openly pledges fealty to the president. To take office, an attorney general and other federal officials must vow: “I do solemnly swear [or affirm] that I will support and defend the Constitution of the United States.” The oath is to the Constitution not to a person, not even to a president.

Even though the Attorney General, U.S. Attorneys, and other federal officials are supposed to work for all of us (we do pay their salaries after all) and not for the president alone, the lines of authority are muddled. The president does have a power akin to an employer; he can remove an attorney general, a U.S. Attorney, a Secretary of State, and other federal officers. Furthermore, in the legal area, since the president has been given the constitutional duty to “take Care that the Laws be faithfully executed. . . ,” he can set the priorities and policies for the Department of Justice and the Attorney General. Of course, if what is commanded is unconstitutional, the AG or the US. Attorneys cannot — consistent with their oath of office — carry out the command. On the other hand, even if the directive is deemed constitutional but unwise, the AG can be expected to be removed if she does not comply with presidential wishes.

The president can then seek a new attorney general, presumably after vetting the candidate on the contested issue, but that also is complicated. The Constitution does not give the president the power to appoint any Attorney General he wants. Instead, it says that the president “shall nominate” candidates to be federal officials. The Constitution goes on to say, “and by and with the Advice and Consent of the Senate, shall appoint” the Attorney General and other federal officials. The appointment power is a joint one of both president and the Senate. The Constitution does not constrain the Senate in how it should use its power. It is only a norm or a convention that the Senate gives great deference to the presidential nominations.

Thus, the Attorney General and U.S. Attorneys inhabit a strange territory filled with inconsistencies. The president can set criminal justice policies broadly or for individual cases. He can remove those who do not follow his directives. Nevertheless, they do not work for him. They serve the country and its Constitution. He does not have the sole power to replace them. Rather, he holds that authority jointly with the Senate.

Something similar can be said for other federal officials. If the Secretary of State does not carry out the president’s wishes, he can be replaced, but the situation for prosecutors is even more complicated. They are members of the bar, and the legal profession has ethical codes that lawyers are supposed to follow if they are going to continue in the profession. The bar can take their law licenses or otherwise discipline lawyers who don’t follow the ethical rules. That happened to some lawyers for unethical conduct in pushing the claims that the 2020 election was “stolen.” Some were disbarred; some had their licenses suspended.

All lawyers in addition to the duties of their job owe a duty to the justice system. For most attorneys, this boils down to zealously advocating for their clients in an honest fashion. For prosecutors, however, it is different. They do not have a client in the traditional sense and their ethical duties include, but do not stop at, being a zealous advocate. Incorporating the language of the Supreme Court, the American Bar Association has said: “The prosecutor is an administrator of justice, a zealous advocate, and an officer of the court. The prosecutor’s office should exercise sound discretion and independent judgment in the performance of the prosecution function. . . . The duty of the prosecutor is to seek justice, not merely to convict.”

Federal prosecutors are, thus, in a strange role. The president can set prosecutorial priorities. They don’t work for the president, but he can fire them. On the other hand, they are to use “independent judgment,” “seek justice,” and use “sound discretion” and not just follow orders. Their ethical path is a difficult one, and not all have followed it. What is clear, however, is that the path can’t be trod if fealty to a person is primary and working for justice with independent judgment is set aside.

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Ozempic Triumph vs. Scientific Defeat (Guest Post from the Spouse)

It has become clear in recent weeks that the “humanoid alien beings” (as a friend calls them) who run the White House have less than zero understanding of the way medical, biological, or chemical science works. It isn’t that they don’t understand scientific facts (okay, not all of us love the minutiae of alkaloid biochemistry), but they don’t understand the sociology, economics, methodology, or history of science. In particular, they don’t seem to know how scientific knowledge accumulates — tiny steps over long periods of time. As a result, the proposed layoffs and drastic funding cuts in the National Institutes of Health and the National Science Foundation threaten to bring scientific progress, particularly in medical science, to a halt.

Elon Musk may think that the design and construction of his electric car sprang full-blown from his brilliant mind. It didn’t. It was the result of incremental increases over time in the understanding of combustion engines, mechanical and electrical engineering, and so on. Similarly, most of us don’t appreciate where life-saving drugs come from, and even those of us who work or have worked in science don’t know the history of most of the drugs we take every day. I certainly didn’t. We don’t know the many, many hours of research and the many years of effort that culminate in these drugs seeing their way into the clinic. So I took a shallow dive into the history of the well-known drug Ozempic to see how it came to be.

This story goes back to research that began in the 1920’s. But, before going there, some basic human biology:

Blood sugar (glucose) levels are carefully regulated in the healthy human body. When blood sugar levels are too high, the pancreas produces insulin to encourage cells all over the body to take up that sugar and either use it or store it. When blood sugar levels are too low, the pancreas produces a different hormone, glucagon, that tells the liver that it’s time to release some of that stored glucose. It’s an important biological yin and yang. Insulin and glucagon are on two ends of a physiological seesaw, keeping sugar levels steady. If the system gets out of whack (as it does in Type 2 diabetes), too much blood sugar threatens the body with myriad catastrophes including organ failure, blindness, immune system dysfunction, etc. etc. etc. The importance of the seesaw to human health and the distressful increase in Type 2 diabetes have meant that interest in insulin and glucagon have been keen since their discovery in the 1920’s.

In the early 1980’s (more than 40 years ago and some 60 years after the discovery of insulin and glucagon) researchers at the National Institutes of Health who were interested in diabetes (already identified as a disease of the pancreas) began screening venoms for possible effects on guinea pig pancreatic cells, the insulin producers. (These days such a study would be called “a fishing expedition” and would be an unlikely candidate for funding.) It was tedious work. Nevertheless, after looking at venom from bees and wasps and snakes and such, the researchers found that venom from gila monsters (those ugly black and yellow reptiles of the US southwest) had a unique effect on pancreatic cells; the cells became enlarged and started producing lots of insulin. In short order they determined that the venom — or something in it — regulated blood sugar levels in animals. 

Around the same time, an American biologist at Massachusetts General Hospital and a Danish physiologist (working separately) were intrigued by glucagon. Reminder: Glucagon is made in the pancreas and promotes glucose release from the liver, thereby increasing blood sugar levels. However, a small piece of the glucagon molecule, which they called glucagon-like peptide-1 (GLP-1), triggered pancreatic production of insulin and…and…and seemed to suppress appetite and trigger weight loss in laboratory mice. Could this be a drug to treat diabetes and curb obesity? Side bar: the technology they used to identify this molecular “fragment” had taken its own sweet time in coming to fruition.

It was a short-ish step to determine that the substance found in gila monster venom was very like GLP-1. In the early 1990’s John Eng at the VA Center in the Bronx found a molecular look-alike to GLP-1 and named it Exendin-4. Later, a researcher at the National Institute on Aging, working with a pharmaceutical company, obtained FDA approval in 2005 for its use in Type 2 diabetes. Side bar: the technology used to purify and get the DNA sequence of this molecule had been developing on a separate track, but they couldn’t have identified the molecule without it.

But there was a problem with both GLP-1 itself and Exendin-4. They had to be injected (bad enough), but they disappeared quickly from the blood, not hanging around long enough to be very effective. Importantly, chemists at Novo-Nordisk came up with a method for changing the molecule so that it stayed active in the bloodstream. Side bar: you get the picture.

But what about obesity? This effort took a different track and gets murky in part because obesity was not yet considered a “disease” or even an eating disorder. Obesity was long considered to be the personal failure of individuals to limit their food intake and/or their refusal to exercise. Another line of research was being done leading to the realization that for many, obesity was a physiological abnormality that just might succumb to drug treatment. And so it is. In short, the same drug (semaglutide, a GLP-1 look-alike) is indicated for both Type 2 diabetes (Ozempic) and obesity (Wegovy).

People are still a bit unsure how these drugs work to increase weight loss and suppress appetite. They just know that they do. There are hints, though, that it involves direct actions in the brain. This observation, in turn, has led to the hypothesis that there could be a link between metabolic imbalance and neurodegenerative diseases such as Parkinson’s disease, Huntington’s, and/or Alzheimer’s. Clinical trials using Exendin-4 on Alzheimer’s-prone patients have begun. However, those trials and this promising line of research will be stopped when NIH research funding is stopped…as it is now.

In short, Ozempic is the result of almost 100 years of research involving incremental discoveries in physiology, chemistry, molecular biology, neuroscience, and research methodology. That’s a long time, but sometimes science takes a long time. These sorts of breakthroughs will take longer or not even occur if research funding is brought to a halt…as it is now.

Posted on by rjonakait

Snippets

I told Lisa the librarian that I thought that all librarians should be named Marian. To my surprise, she did not know the reference.

Steve Bannon on his podcast said: “A lot of MAGAs on Medicaid. . . . Medicaid is going to be a complicated one. Just can’t take a meat ax to it, although I would love to.” How revealing. Bannon, and no doubt many like him, are not concerned about our healthcare system generally, and certainly not about healthcare for those in the country’s bottom economic quarter. (Almost 25% of Americans get assistance from Medicaid.) He is only concerned because many Trump supporters get Medicaid. (If they weren’t MAGA, would he describe them as on the government dole?) Otherwise, he would only want to destroy Medicaid.

Congressman Rich McCormick, a Republican from Georgia, said that the GOP could do a better job of showing “compassion.” Is there a compassion switch? Can you “show compassion” if you don’t have it in the first place?

“All political parties die at last of swallowing their own lies.” John Arbuthnot.

The fired government workers do get compassion from many, as they should. Most government employees, like most Americans, live paycheck to paycheck, and the sudden loss of a job for them and their families is a tragedy many of us can immediately comprehend. What we don’t see is the harm down the road. What are the consequences if weather forecasts become worse, or if waiting times at VA hospitals are longer? How do you measure what is foregone from lost medical research or the increase in waste, fraud, and corruption that results from fired IRS workers?

We may not know precisely what is lost from the firings, but we know that foreseeable losses will come. On the other hand, there are always unintended consequences that are not foreseen. I was reminded of that from Troy Senik’s biography, A Man of Iron: The Turbulent Life and Improbable Presidency of Grover Cleveland. Senik writes that the Pendleton Civil Service Reform Act of 1883 sought to eliminate patronage for appointment to government jobs. Under the patronage system, those who got employment were assessed a portion of their salaries to kick back to the political parties who secured the positions. Senik says that it was estimated that up to 75% of party funding came from such assessments. With that spigot turned off, parties turned to wealthy individuals and interest groups to fund electoral politics. Thus, job appointments based on merit had the unintended consequence of providing more power to the rich.

V13: Chronicle of a Trial, a magnificent book by Emmanuel Carrère (translated from the French by John Lambert), contains compassion, but also horror, inhumanity, humanity, bewilderment, and much more. On November 13, 2015, jihadists launched attacks in Paris. Luckily, if there was anything like luck that day, suicide bombers arrived late to a packed football game and could not get in. They blew themselves up outside where the crowds were thin. Others allied with them shot randomly at restaurant terraces and cafes killing more, but the major carnage was at the Bataclan theatre, a concert venue of 1,500 hosting apparently a mediocre American rock group, Eagles of Death Metal. Nearly a hundred people were slaughtered in the hall. Six years later a trial started, which took on the name V13, for Friday (Vendredi) the Thirteenth, the day of the attack. Carrère reported on the nine-month trial for a French magazine, and those columns form the basis of the book. At times extremely hard to read (“confetti of human flesh”) but always compelling, V13 is remarkable. Reading it now, I could not help but think about October 7 and its aftermath. One of those on trial in Paris (the defendants were all second stringers since all those who did the actual killing were dead) maintained that the massacres were in response to the loss of innocent lives in Syria from French bombings and said, “Everything you say about us jihadists is like reading the last page of a book. What you should do is read the book from the start.”

Posted on by rjonakait

Snippets

Hey, DOGE, a suggestion for you. A news report said that Secretary of Defense Pete Hegseth has government housing. We taxpayers are on the hook for a $49,000 paint job and six figures for renovations. Why? Hegseth has a salary of $235,000, almost three times the median household income in this country. People making as much as Hegseth are responsible for their own housing. Why shouldn’t government workers be, too? DOGE, get an executive order selling off all that housing. How much could we save?

Part of the renovations are apparently for secure information facilities. What? I thought Hegseth was adamant about not working remotely. I assume that he has secure facilities at his office. Is he planning to work at home instead of the office?

Along the same lines, DOGE. How many government workers have a car and driver? We ordinary taxpayers, even if we make $235,000, have to handle our own commutes. Why are government workers better than we are? How much can be saved by jettisoning the cars and drivers? (And do those who have a car and driver pay income tax on the value of that service?)

A wise person said: “There should be a happy medium between government running private business and private business running the government.”

I assumed it was on old sign that read: “Full Service Unisex Hair Care.” Hasn’t Trump outlawed all unisex activities?

We do have savings as the administration follows Mark Twain, who said, “Truth is such a precious article let us all economize in its use.”

I could never be a birder if you have to be able to say “blue-footed booby” without suppressing a smirk or a chuckle. Or “tufted titmouse.”

With all the brouhaha over that gulf, I wonder: Do the French call it the English Channel?

Before going to sleep, I always walk slowly backwards around my bed three times. I do this because it keeps the polar bears away. I know this works because I have never had a nighttime ursine invasion. Some of Trump’s executive orders remind me of my ritual. For example, one EO forbids undocumented aliens from receiving federal benefits. However, before the recent order, the undocumented did not qualify for any such funding, and nothing indicates that the migrants have gotten anything substantial from fraud. In other words, before the order, no federal benefits for the undocumented, and after the order, no benefits for the undocumented. Even so, I expect that the success of the order will be touted. Another example: Trump flamboyantly signed an executive order to end Covid vaccine mandates in public K-12 schools. However, schools do not now have such mandates. I still expect the fanfaronade about the order’s success. And still my slow backward walk has kept the polar bears out of my bedroom. However, I am searching for a way to bring giant pandas in to snuggle up with at night.

Every year—well, three out of four years—I purge and fast on February 29, 30, and 31.

Posted on by rjonakait

Our Rubicon Moment?

Friends asked me to discuss the “constitutional crisis” that the media seems to think is imminent.

My starting point is to explain that the Constitution is not static. It has changed in big and small ways; scholars have identified three major constitutional transformations.

The first came before we even had a national constitution. The newly-independent states were bound together by the Articles of Confederation, which were not considered adequate for governing the emerging nation. Therefore, men got together in 1787 in Philadelphia ostensibly to reform those Articles. Instead, they drafted a new constitution which was adopted by the requisite nine states the next year. A new government came into being. Our government today depends on that eighteenth century document, and it is controlled by the constitution much as it was back then.

Early on that founding document was seen as needing changes. Some states only ratified the Constitution with the understanding that a Bill of Rights would be added. The first Congress proposed twelve amendments, ten of which were adopted and went into effect in 1791. These additions mostly announced rights people assumed they already had and did not change the structure of the government. However, a decade later a major flaw in the document was exposed by the election of Thomas Jefferson and Aaron Burr. As a result, the Twelfth Amendment was adopted modifying the electoral college. From its inception, therefore, the Constitution has been subject to change.

The first significant transformation of the Constitution, however, came from the Civil War and its aftermath. The war occurred partly because of a major flaw in the document itself. Instead of confronting the issue of slavery, the founders tried to avoid it or make feeble compromises about it. As a result, slavery was not merely a stain on the fabric of the Constitution but woven into it. Various factions pulling at the threads and cords of slavery from all directions challenged the constitution, and war came.

In the war’s aftermath, three amendments to the Constitution were passed. The Thirteenth Amendment abolished slavery. The Fifteenth Amendment granted Black males, but not women of any color, the right to vote. These two amendments were transformative, but they were only partially successful. Slave-like practices continued to exist in the country, and within a decade of the adoption of the Fifteenth Amendment, the right to vote was stripped from most Blacks.

The Fourteenth Amendment, although it has several provisions, reshaped our Constitution by commanding that no state “shall deprive any person of life, liberty, or property without due process of law; nor deny to any person within its jurisdiction the equal protection of the laws.” The original Constitution did little to constrain the states in their treatment of inhabitants. The Fourteenth Amendment, as interpreted by the Supreme Court, changed that. For example, the Court held that the amendment’s due process clause prevented a state from taking a person’s property without just compensation. In the early twentieth century it held that the state could not abridge free speech. Over time, the Court increasingly prohibited the states from interfering with rights guaranteed in the Bill of Rights. The Court, relying on the Fourteenth Amendment, also said segregated state schools were unconstitutional and that states must afford one person, one vote. The constitutional crisis of the Civil War produced a Fourteenth Amendment that transformed the relationship between courts and individuals by expanding and clarifying constitutional rights.

The next major constitutional transformation came during the Great Depression. The Supreme Court had found unconstitutional many state and federal laws regulating businesses. This crescendoed during Franklin Roosevelt’s first term when the Court deemed unconstitutional much New Deal legislation that had been passed by Congress to alleviate the harsh economic conditions. FDR responded by proposing that the Court be expanded. Critics called it “court-packing.” Although the causes are debated by historians, lo and behold, after the court-packing proposal, some justices modified their opinions and now upheld federal powers to regulate business and other activities. The Civil War transformation expanded judicial powers to protect individuals and entities from the government. The Great Depression transformation expanded the power of the federal government to regulate activities affecting “interstate commerce,” which has been broadly defined. The decisions of the New Deal Supreme Court provide the basis for much of the federal government’s regulatory power today.

So. Are we now in the midst of another constitutional crisis? Are we due for another constitutional transformation? I see not one possible scenario, but several.

Conservatives look at our government and see a bloated bureaucracy that was not contemplated by the Constitution. It is entrenched but not elected. That bureaucracy, though authorized by Congress and the president, often seems to act independently of Congress and, more importantly, the president. Although it appears to be part of the executive branch of the government, the bureaucracy often sets and follows its own guidelines and policies. Thus, conservatives see a bureaucracy that is too often resistant to the policies of the president, and they find this in violation of the constitution. This unconstitutionality in the conservative eye must be put to rights. A constitutional transformation is needed to restore the balance that our Constitution contemplates where the president sets and enforces executive branch policies. And, under Trump, conservatives maintain we are seeing the beginning of that needed constitutional transformation.

On the other hand, some, but not all, liberals see a different potential constitutional crisis. Many of Trump’s actions and orders, they claim, have been in direct conflict with specific provisions of the Constitution (e.g., birthright citizenship), have been in violation of the separation of powers, or have violated the constitutional duty of the president to “take care that the laws be faithfully executed.”  And while conservatives see a constitutional crisis in an unelected bureaucracy, liberals see a crisis in the unfettered authority exercised by an unelected Elon Musk who has not been appointed to a Senate-confirmed position the Constitution seemingly requires.

Other liberals may be concerned about the administration’s actions, but they don’t see a present constitutional crisis. They see the system working because the courts have been hearing challenges to Trump’s and Musk’s orders. This is the normal constitutional process, and Trump has said that he will follow the judicial process. Almost all the court rulings have been in the federal district courts, which are the lowest level of federal courts. Following decisions in the district courts, those findings can be appealed to the Court of Appeals. Then the losing litigant may seek to have the Supreme Court hear the matter. (There is no right to have the Supreme Court hear these cases; it is in the Court’s discretion.) Many maintain that as long as this process is being followed, there is no constitutional crisis.

Even so, liberals who don’t see a present crisis, are concerned about a future constitutional transformation. Many, probably most, constitutional scholars believe that under existing Supreme Court rulings, many of Trump’s actions violate the Constitution or existing laws. The first fear is that the current conservative Supreme Court will ignore or overturn the precedents and uphold Trump’s actions. That is, that the Supreme Court will reinterpret the Constitution and laws to give the president even more power than he now has. This will, in effect, remake the Constitution by taking away congressional authority and individual rights and make an already powerful president even more powerful. As it did with its presidential immunity decision, the Supreme Court could transform our government to make the president more kingly, more authoritarian.

The other liberal fear is not of the Supreme Court but of Trump himself. Even though he has said otherwise, the fear is that Trump will either not use the appellate process and just keep bulldozing ahead, or even if he does follow normal procedures, he will not obey Court orders that go against him. He will ignore or defy the judiciary. Of course, he said he wouldn’t do that, and he did not disobey the courts in his first term. However, those around him have suggested that he will this time if courts don’t rule his way. And just as you can find Trump statements that he will honor the judicial process, like the devil quoting the Bible, you can find other Trump pronouncements, such as his recent statement: “He who saves his Country does not violate any laws.”

Presidential defiance of the courts would be a true constitutional crisis, perhaps a fatal one. His recent statement about not committing illegalities when saving the country is ascribed to Napoleon, but precedents go back further into history. Julius Caesar broke the law and illegally marched his troops, loyal to him more than to the nation, across the Rubicon and into Rome. The fall of the Roman Republic began, and a dictatorship took its place.