Coffee Break: Autism, Universities, Gene Therapy for HD That Works, More Anti-Vax Nonsense, and Making America Greater, or Not.

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Part the First: Tylenol and Autism.  Earlier this year the Secretary of Health and Human Services promised to identify the cause of autism by September.  This week he delivered, with days to spare.  Who would have thought the cause had been hiding in plain sight all this time?  Tylenol (acetaminophen) is the culprit.  Previous studies of various power have shown small correlations between acetaminophen use by mothers during pregnancy and neurodevelopmental disorders.  This was covered by Naked Capitalism previously here and in other posts.  A more recent study of this relationship, or lack thereof, was highlighted in Nature on September 22 in response to the announcement by the president and RFKJr:

The painkiller acetaminophen, or paracetamol, is one of the most widely taken drugs during pregnancy, used by roughly half of all pregnant women worldwide.  But US president Donald Trump said Sunday that he thinks the medication is “a very big factor” in autism.  And both the Washington Post and Politico report that an announcement from the Trump administration today will raise concerns about a link between autism and use of Tylenol by pregnant women. The details of the announcement are not yet clear. (lightly edited)

In a press briefing ahead of the announcement, White House press secretary Karoline Leavitt declined to provide specifics about the administration’s conclusions.  “This will be a powerful display of how the entire Trump administration is committed to addressing root causes of chronic conditions and diseases,” she said.  When asked by a reporter whether an announcement linking acetaminophen and autism might confuse pregnant women, Leavitt told reporters not to jump to conclusions based on media reports that the White House had not yet confirmed.

On the other hand:

“There is no definitive evidence to suggest that paracetamol (acetaminophen) use in mothers is a cause of autism, and when you see any associations, they are very, very small,” says James Cusack, chief executive of Autistica, a UK autism research and campaigning charity in London, who is autistic. “At the heart of this is people trying to look for simple answers to complex problems.” (emphasis added)

This has been covered well over the past few days, so there is no need to recapitulate everything, but one of the best studies currently available agrees with James Cusack of Autistica.  This research was published in JAMA in April 2024: Acetaminophen Use During Pregnancy and Children’s Risk of Autism, ADHD, and Intellectual Disability (open access):

Question. Does acetaminophen use during pregnancy increase children’s risk of neurodevelopmental disorders?

Findings. In this population-based study, models without sibling controls identified marginally increased risks of autism and attention-deficit/hyperactivity disorder (ADHD) associated with acetaminophen use during pregnancy. However, analyses of matched full sibling pairs found no evidence of increased risk of autism (hazard ratio, 0.98), ADHD (hazard ratio, 0.98), or intellectual disability (hazard ratio, 1.01) associated with acetaminophen use.

Meaning. Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in other models may have been attributable to confounding variables.

Power and sample size are not an issue here. Nor is this a meta-analysis of studies of varying power and significance.  Moreover, this study was done in Sweden, where the healthcare system is rational and nearly universal.  This vitiates the likelihood of familial and nonfamilial/societal confounders that would undoubtedly skew results in the United States:

Objective. To examine the associations of acetaminophen use during pregnancy with children’s risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability.

Design, Setting, and Participants. This nationwide cohort study with sibling control analysis included a population-based sample of 2,480,797 children born in 1995 to 2019 in Sweden (185,909 children exposed during pregnancy), with follow-up through December 31, 2021.

Exposure. Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records.

Conclusions and Relevance. Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

The results are clear, and readers who want to look carefully at the data should do so.  The study is well done.  The very minor correlations of acetaminophen use with a neurodivergent outcome may be statistically significant at the far margin, but they have vanishingly small clinical relevance.

But more importantly, there is one confounding issue with acetaminophen use in general.  Acetaminophen is very toxic, especially for an over-the-counter drug.  From the National Library of Medicine StatPearls article (public access):

Acetaminophen is one of the most commonly used analgesics and antipyretics.  Although relatively safe at therapeutic doses, acetaminophen poisoning causes hepatic necrosis. Acetaminophen toxicity is the second most common cause of liver transplantation worldwide and the most common cause of liver failure in the United States.  Responsible for 56,000 emergency department visits and 2600 hospitalizations, acetaminophen poisoning causes 500 deaths annually in the United States.  Notably, around 50% of these poisonings are unintentional (acetaminophen is frequently used in suicide attempts), often resulting from patients misinterpreting dosing instructions or unknowingly consuming multiple acetaminophen-containing products.

Physicians have misinterpreted the dosing recommendations, too.  I first learned of this toxicity by reading an article about a person who attempted suicide by drinking several bottles of a cold medicine containing acetaminophen.  When he woke up the next morning, he was relieved he had not been successful.  Nevertheless, he died of acute liver failure within two days.  Thus, acetaminophen should always be taken directly under the care of a physician.  This “safe” pain reliever should be avoided unless absolutely necessary, and there are strong indications for acetaminophen.

As for the causes of autism, there will be many, mostly linked to genes in a variegated web of genetics and environment.  There are currently 958 entries using “autism” as the query in Online Mendelian Inheritance in Man (OMIM.org).  Some are undoubtedly off topic or spurious, but the answers to autism – not the answer – lie there.  The environment provides the soil in which the condition develops.  And these answers will be hard to find, because experiments cannot get us to the answers.  Contrary to current political simplemindedness, there can be no simple answer to such a complex problem.

For an interesting and affecting take on people with autism, see Jessica Wildflower from earlier this week: They’re Going After Autistic People for a Reason.

Part the Second. The Trouble with Universities.  This has been brewing for a long time, with the recent attacks on universities and colleges being the tip of a large iceberg.  I have been an academic of one sort or another for most, but not all, of my working life.  For someone who wants to come back in his next life as a Fellow of All Souls, the spectacle of universities losing the plot so badly has been difficult to watch.  But given the neoliberalization of everything, this decline was inevitable.

The Current Administration believes universities are havens of that most protean of all malefactors, the “radical leftist,” with the meaning of radical and leftist misunderstood.  It is undeniable that many of us, but certainly not all, who believe the seven liberal arts are the foundation of human knowledge tend to the left.  This includes those who view science, as in natural history of the living and nonliving physical universe, as an extension of the seven liberal arts.

I have never noticed the absence of conservatives on campus, though.  Fraternities and sororities are full of them.  Business and law schools and medical schools, too.  Ditto for engineering schools.  Conservatives are usually well represented in the political science department and are not uncommon in other departments in the humanities and social sciences.

Most students, though, are, and have been for a long time, interested in little more than a credential.  Oh, and a good time.  Even in my youth, the number of students who had the guts to take physical chemistry or an upper-level history courses in Early Modern Europe and the Renaissance, each with a reading list of ten books in a ten-week quarter was vanishingly small.  They missed out, though.  But, I fully understand that, just as I understand students who bragged about never having stepped foot in the library.  The Prince or Castiglione’s The Book of the Courtier would not be useful if plans are to return home and take over the family business and eventually enter politics.  Or would they?  In any case, these days deep reading is two scroll-downs on an iPad screen, or maybe an iPhone.

How universities came to be — and why they are in trouble now is a long comment in Nature by Philip G. Altbach.  He makes any number of good points: Universities are too big, too diffuse, too expensive, unserious.  But the primary problem with colleges and universities since World War II has been “credential inflation,” as those of us who must deal with any Department of Human Resources know all too well.  The best senior staff members I have worked with for the past forty years went to work out of high school, but I digress.

The necessary concomitant of credential inflation has been grade inflation where students (and more importantly, their parents) are considered customers first, last, and always instead of students.  The C-minus of 1955 has become the A-minus of 2025.  This is true at Harvard and the local state university that was a perfectly good and essential teachers’ college in living memory (it is not an accident that the best teachers I had in Grades 1-12 were graduates of these schools instead of the College of Education of the “flagship” state university).  This has been followed by big money, which has turned the larger American universities into mini-resorts and wannabe football factories.  The student loan scam will be another big factor in the dissolution of higher education, but that seems to have reached the Herb Stein Limit: “If something cannot go on forever, it will stop.”

I have no idea what comes next, but it will be different, and somebody’s soup bowl will get shattered.

Part the Third. What Comes Next for Universities Might Be This.  The New Model Institute for Technology and Engineering (NMITE) in Hereford.  This article, again in Nature, explains in No lectures, exams, essays: inside a twenty-first-century university.  The tagline is the key:

Some innovative higher-education institutions are reimagining pedagogy by prioritizing local needs over research and international student recruitment.

And this is what NMITE does:

The institute is trying something rare in UK higher education. It is building a new kind of university from the ground up — one that promises to address the skills shortage in engineering, rebalance regional access to education and rethink how engineering is taught in a city with one of the lowest university participation rates in England.

“Broadly speaking, the approach to learning at NMITE is directly against the traditional wisdom in the higher-education system,” says Norman, who campaigned for the university to be set up and became its chair in January. “We don’t chase international students. We focus on raising the skills and intellectual achievement of kids in Britain.”

NMITE is not, and did not set out to be, a research-intensive institution; instead, it concentrates on undergraduate teaching, industry-led projects and preparing graduates for immediate employment.

It now has around 50 members of staff. Almost all live locally; most of the administrative staff members have long been based in the area, whereas most of the academic employees relocated to join the institute. NMITE offers a small number of specialist degrees — currently integrated bachelor’s and master’s in engineering.  The latter is designed to meet the UK Engineering Council’s Chartered Engineer requirements and is delivered as an accelerated programme, taking three years instead of the usual four.

Graduates will be fully prepared to become professional engineers.  Wendell Berry has said many times that universities should offer a major in “homecoming.”  He is correct.  As the world gets smaller in the coming inconvenient apocalypse, we should look for that.  Or our children should.

Part the Fourth: A Breakthrough in Huntington’s Disease.  The gene for Huntington’s disease (HD) was identified in 1993 through the heroic work of Nancy Wexler and the Hereditary Disease Foundation.  Now, thirty-two years later there is some hope for Huntington’s disease patients:

An experimental gene therapy from uniQure slowed the progression of Huntington’s disease by 75% after three years — study results reported Wednesday that are likely to support the first approval of a genetic treatment for the rare neurodegenerative condition.

For people living with Huntington’s, an effective, one-time therapy that significantly slows the loss of muscle control and cognition around mid-life could preserve years of quality relationships and gainful employment that would normally be lost to the disease.

How does the therapy work?  HD is an autosomal dominant disease.  That is, a person who inherits one mutant gene from one parent will get the disease eventually.  The other chromosome produces the normal protein huntingtin.  The “gene” in this gene therapy produces a small RNA molecule called a microRNA.  When this microRNA binds to the mRNA that directs production of the mutant huntingtin, production of the toxic, gain-of-function protein is down-regulated.  This is not a cure, but it is likely to be an intervention that works:

The treatment uses a harmless virus to deliver the recipe for making a short RNA sequence known as a microRNA directly into cells in the affected parts of the brain. The microRNA is designed to ‘muzzle’ the defective huntingtin gene — and stop the cells producing the faulty protein — by blocking the molecular instructions encoded by the gene, known as mRNA.  Once delivered, the virus-encoded instructions stay inside the cells, which continue to produce the therapeutic microRNA.  The discovery of microRNAs was feted with a Nobel Prize last year, although the technology has yet to yield any approved medicines.

Administering the treatment requires a lengthy surgery in which clinicians use magnetic resonance imaging to precisely place a cannula through small holes in the skull. The therapy is then infused slowly into the striatum, a part of the brain that is among the first and hardest hit by Huntington’s disease.

Yes, this is expensive, but we can afford it.  Treatment is not a cure but early gene therapy may postpone disease onset for a long time.  MicroRNAs were identified about thirty years ago, and scientists considered them pieces of junk RNA.  About twenty years ago they were shown to be important in gene regulation and expression.  Today they are a treatment for a horrifying, inexorable disease.  John Horgan made a few good points in his The End of Science, but when microRNAs and CRISPR are used to treat disease, I am able to resist the urge to take the book down off the shelf and read it again.

Part the Fifth. The Hepatitis B Vaccine Controversy.  The question is, should babies be vaccinated against HepB?  Some say no, because HepB is usually a sexually transmitted disease.  But not always.  There is scant evidence that the HepB vaccine is harmful, and it does work.  While driving to a meeting in the dark early Thursday morning, I listened to this short report on Morning Edition: Experts say Trump’s guidance on hepatitis B vaccine and babies is dangerous.  Key points:

Hepatitis B is a virus that attacks the liver. The disease has no cure and can lead to liver cancer, cirrhosis and death. And the risks of these outcomes are much higher for people who get infected as infants.

About 25% of children who develop chronic hepatitis B will die of their infection.

Before the U.S. began universally vaccinating newborns in 1991, some 18,000 children each year became infected before the age of 10. About half were infected by their mothers at birth. The other half got it from somewhere else.

The virus is found in blood, saliva, even tears, and it can live on surfaces for up to seven days.  A child with a wound who comes into contact with that surface even days later could become infected.

Since HepB vaccination became routine in the U.S., case rates have plummeted by 99% among people age 19 and younger.

To recap: Before 1991, 18,000 children per year became infected with HepB before the age of ten.  Approximately 4,500 of them could be expected to die of HepB-induced hepatitis.  Until there is evidence the HepB vaccine is dangerous to small children, there is no reason not to vaccinate early.  This is not a difficult concept.

Part the Sixth. The Future of American Science.  The meeting I was driving to when I heard the HepB vaccine story was a conference of young researchers sponsored by a national private biomedical research and advocacy agency.  The attendees were from research institutions across the United States and have plans to go to medical school or graduate school and become physicians or scientists or clinical research coordinators and directors.

Virtually none of these young researchers have parents who are paid-up members of the Professional Managerial Class (PMC).  That is the rationale for the program.  One wonders how in the current political climate it will survive to introduce the next cohort of first-generation college students to a life in medicine and/or biomedical research.  My role at the meeting was to talk to students interested in a career as a scientist instead of physician, i.e., those who want a PhD instead of an MD.  For an hour I asked questions of them, and they responded with questions directed to me.  Our hour together was much too short!

Last year at the same meeting, a small group was inspiring.  This year a much larger group was even more inspiring.  But this week’s meeting was dispiriting at the same time.  These young researchers pay attention.  They saw what happened in their institutions as the berserkers did their damage earlier this year.  These young men and women are seriously committed to the life of a scientist, or they would not have been in the program and at the conference.  They asked great questions.  They were engaged and enthusiastic.  They have aspirations that will would truly make America greater in the future.  Will they ever get the opportunity?  At the moment that seems unlikely.  And as my late grandmother, philosopher in the vernacular, would have put it, “That is a sin and a shame.”