Coffee Break: Genes and Disease, Workslop Passing for Science, Nobel News, a Labor Party in the US, and Our Sick Politics

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Part the First: Genes and Disease.  The Current Administration announced early in its first year that they would know the cause of autism by September.  They met their deadline when the Secretary of Health and Human Services announced his result, which has been hiding in plain sight all this time: Tylenol.  Actually, not so much.  And every legitimate scientist knows this, as does every other person who stops and thinks about it, if only for a moment.  Tylenol (acetaminophen in the USA and paracetamol in Europe) might have some spurious correlation with autism on occasion (and the connection might be that the mother was ill during pregnancy and used Tylenol).  But there is no doubt the causes of autism are multifactorial and contingent upon the environment in which the autistic person has lived.  Most of the multiple factors are genetic, as in certain variants of certain genes in specific genetic backgrounds will tend to lead to behaviors that are on the autism spectrum.  That is the conditional nature of autism.

Complex problems cannot usually be solved by simple answers, unless we are talking about Alexander the Great taking his sword to the Gordian Knot.  Complex problems are never solved by simplistic answers, which seems to be the preferred choice of the Current Administration to every problem, mostly imagined (tariffs, on coffee, for example; DOGE; conflation of criticism of the State of Israel with antisemitism).

Complexity is the nature of genes and disease, where the correspondence between a genetic variant and disease is often inscrutable if not altogether unknown.  This is not to deny the direct connection between genes and certain diseases.  Sickle cell disease is caused by one mutation in the beta chain of hemoglobin, the protein that carries oxygen in red blood cells.  People with one copy of this mutation have sickle cell trait, a mild form of the disease.  People with two copies of the mutant gene have sickle cell disease.  This has been known since the 1940s and the specific mutation was identified in the 1950s.  The most common form of cystic fibrosis is caused by the deletion of only one amino acid in the protein that has been named CFTR (phenylalanine-508 of 1,480 total amino acids; I can hear them now – that’s only 0.07% of the protein, how can the effect be that serious for such a small difference?).  People with two copies of a severely defective gene for adenosine deaminase (ADA) lack an immune response and the only cure is a bone marrow transplant.

The complex relationship between genes and disease is covered very well in 1 gene, 1 disease no more – acknowledging the full complexity of genetics could improve and personalize medicine by Santhosh Girirajan of Penn State.  For the history minded, “1 gene, 1 disease” is an echo of “one gene, one enzyme” going back to the Nobel Prize-winning research published in 1941 by George Beadle and Edward Tatum using bread mold as their experimental organism.  Beadle and Tatum were not strictly correct, either.

Genetic inheritance may sound straightforward: One gene causes one trait or a specific illness. When doctors use genetics, it’s usually to try to identify a disease-causing gene to help guide diagnosis and treatment. But for most health conditions, the genetics is far more complicated than how clinicians are currently looking at it in diagnosis, counseling and treatment.

Your DNA carries millions of genetic variants you inherit from your parents or develop by chance. Some are common variants, shared by many people. Others are rare variants, found in very few people or even unique to a family. Together, these variants shape who you are – from visible traits such as height or eye color to health conditions such as diabetes or heart disease.

In our newly published research in the journal Cell, my team and I found that a genetic mutation involved in neurodevelopmental and psychiatric conditions such as autism and schizophrenia is affected by multiple other genetic variants, changing how these conditions develop. Our findings support the idea that, rather than focusing on single genes, taking the whole genome into account would provide insight into how researchers understand what makes someone genetically predisposed to certain diseases and how those diseases develop.

While a primary variant might trigger a disease, secondary variants can alter how that disease develops and progresses. Think of it like a song: The melody (primary variant) is the main part of the song, but the bassist and drummer (secondary variants) can change its groove and rhythm.

That’s why two people with the same genetic mutation can seem so different. One person might have severe symptoms, another person mild symptoms, and another none at all. These variations can even occur within the same family. This phenomenon, called variable expressivity, arises from differences in the secondary variants a person has. In most cases, these variants amplify the effects of the primary mutation. A higher number of secondary variants on top of a primary variant generally leads to more severe disease.

This article from The Conversation is a very good article – one of the best I have ever read – for the general reader on the complex relationships between genes and disease.  The foundation paper is Genetic modifiers and ascertainment drive variable expressivity of complex disorders (open access).  It is very technical but the pictures really are worth a thousand words, when you have time.  Go directly to Figure 4 for a glimpse at the complicated networks associated with complex disorders.  My slowly developing solitary research on the protein network that led to animal multicellularity has similar networks, which are difficult to build but are essential to understanding.  Keeping up with current developments in real science is more difficult that doing so with metascience of the political kind:

This complexity increases for neurodevelopmental disorders, where the combined effects of primary and secondary variants with differing frequency and effect sizes explain their broad heterogeneity. For example, recent studies found contributions of polygenic risk to phenotypes of individuals with pathogenic copy-number variants (CNVs), such as schizophrenia risk in 22q11.2 deletion individuals. Ascertainment may also contribute to variable expressivity, as many pathogenic variants are enriched among individuals across disease ascertainments but lead to other consequences in different populations. For example, the autism-associated 16p11.2 deletion is also associated with obesity as well as musculoskeletal, and renal features in the general population.

I wonder if Tylenol is also causally connected to obesity, and musculoskeletal and kidney disease?  Actually, I don’t.  But one other aspect of this research should be noted.  The paper is in Cell, which is one of the Big Three biomedical journals along with Nature and Science (for good and sufficient reason, despite the occasional fumble by each) and has 75 authors with 33 institutional affiliations in nine countries (USA, France, the Netherlands, Italy, Belgium, UK, Australia, Estonia, and Switzerland).  This is an example of Big Science in fundamental biology that worked, on an extremely important subject.  It could not have been done otherwise on a relevant human time scale.  The directives from the Current Administration against such collaboration in the future will have malign effects, even if they go unrecognized.

The causes of autism, and other diseases with multifactorial origins and presentation will come out of research like this, despite what the simpletons leading our research and healthcare systems believe.

Part the Second: Where Will Biomedical Research be Performed in the Future? Most likely in the eight other countries on the list of affiliations above, plus at least fifty more.  And all will be led by China.  Expect this ad from Nature to attract several thousand applications, most of them from the United States.  Four years in Barcelona to get a PhD will sound pretty good to ambitious young scientists:

Why join the Centre for Genomic Regulation?

• Work alongside world-class scientists in one of Europe’s leading biomedical research institutes
• With just over 400 people on campus and nearly 70% of students coming from abroad, you’ll join a truly international environment where collaboration and creativity thrive
• You will access state-of-the-art core technologies in genomics, proteomics, bioinformatics, imaging, and more
• We are housed in the heart of Barcelona, with our science having privileged views over the Mediterranean Sea. Students enjoy a lively community of international PhD students, with structured training programme, symposia, retreats, beach volleyball, yoga, choir, and monthly institute-wide events.

Programme Highlights:

• Fully funded 4-year PhD positions in top-level research groups with employment contract, competitive salary, health coverage, and full social security benefits.
• Multidisciplinary projects across molecular biology, genomics, systems biology, bioinformatics, and related fields
• Training in scientific, technical, entrepreneurial and transferable skills
• Access to state-of-the-art core facilities and international collaborations
• Career development support and mentoring throughout the programme

Four years in Barcelona, learning Spanish and Catalan and living very well if not extravagantly.  What is not to like about that?

Part the Third: State of Scientific Literature, Continued.  First it was online, open-access, pay-to-publish anything predatory journals on Beall’s List.  Some of the big players remain, making big money for their owners.  They are not difficult to spot for anyone paying attention.  My colleagues were slow on the uptake regarding predatory journals after the first legitimate online journals appeared in the early-2000s.  These journals were a signal advance – faster and less expensive than legacy journals, but with the same editorial standards and expectations.  Now we have paper mills and AI-generated “scientific” workslop (leading word of the year candidate) clogging up science, as reviewed in this article from Nature, Low quality papers are flooding the cancer literature – can this AI tool help to catch them?  The pollution of cancer research, what could go wrong?

An artificial intelligence (AI) tool that scans manuscript titles and abstracts has flagged more than 250,000 cancer studies that bear textual similarities to articles that are known to have been produced by paper mills. These businesses produce fake or low-quality research papers and sell authorships.

Articles produced by paper mills often include fabricated data, duplicated images and weird phrases, which are strange wording choices used to evade plagiarism detectors. Integrity specialists and sleuths can spot these flaws, but the process is time-consuming and, in many cases, the involvement of paper mills cannot be proven so quantifying the scale of the problem is difficult.

Caution is warranted, but:

After screening abstracts and titles, the AI tool gave each article a probability score of how much it resembles suspected retracted paper-mill products. In a test of 276 retracted papers and 275 genuine papers that were not included in the training data, BERT was 91% accurate. The false-negative rate — the share of paper-mill articles that the tool failed to identify — was about 13% (37 out of 276). The false-positive rate — the number of genuine papers that it flagged incorrectly — was around 4% (12 out of 275).

The AI tool was then used to screen 2.6 million cancer-research papers — identified from the PubMed database of biomedical literature — that were published in 11,632 journals between 1999 and 2024. The tool identified 261,245 of the papers as suspected paper-mill articles, most of which were fundamental research studies. (Someone needs to do this experiment with COVID papers)

Why “fundamental research studies”?  These are the easiest when the goal is making “stuff” up.  The training sets in this research are critical, but early results seem valid.  I tend to side with the gloomiest interpretation of AI.  Will it be the next big thing or the next big bubble that fills the world with workslop, perhaps a direct analog of the F-35?

So, in addition to being a military disaster, the F-35 many also prove to be a foreign relations disaster as well. F-35 boosters in the United States sold the jet to the leaders of these countries with elaborate pitches of the combat capabilities they planned to deliver. There were also promises made early in the process about the program’s affordability, which seem comical today. The next time an American attempts to sell a “transformative” weapon abroad, they shouldn’t be terribly surprised if a potential customer expresses skepticism. F-35 customers have paid a fortune above the quoted price, receiving only a fraction of what was promised. The United States may find a shrinking market for weapons exports in the years ahead.

This should be a moment of deep reflection for the entire national security establishment. The F-35 was never going to live up to expectations because its very concept was deeply flawed. Trying to build one jet that could serve as a multi-role aircraft to meet the needs of just a single military branch is a highly risky proposition. When you try to build a single jet to meet the multi-role needs of at least 15 separate militaries, while also being a global jobs program and political patronage scheme, you get a $2 trillion albatross.

Part the Fourth: The Nobel Prize in Physiology or Medicine.  Note that physiology comes before medicine.  I had planned to write a short explanation of the 2025 award, but Dr. Steven Novella has done a much better job than I could ever do: Nobel Prize in Medicine: Peripheral Immune Tolerance:

The 2025 award for physiology or medicine goes to three researchers, Mary E. Brunkow, Institute for Systems Biology, Seattle, USA, Fred Ramsdell, Sonoma Biotherapeutics, San Francisco, USA, Shimon Sakaguchi, Osaka University, Osaka, Japan, for their work on what is known as peripheral immune tolerance.

As yet there are no approved therapies based on Tregs (regulatory T cells of the immune system), but there are several in early clinical trials. These include treatments for autoimmune diseases, degenerative diseases, and organ transplantation rejection. This is yet another example of the typical 2-3 decade delay from basic science discovery to clinical application. That is how long it takes to fully understand the implications of a new discovery and translate it into an actual treatment.

It also demonstrates that basic scientists just following their curiosity can make discoveries with profound implications. And it further shows how modern science, including medical science, often progresses as a collaboration of different labs and scientists, and increasingly an international collaboration. This is why it is so tragic and short-sighted that the current administration has cancelled all NIH subgrants to international collaborators. This is already negatively impacting promising research.

Nothing to add to Dr. Novella’s conclusion.  The results of this research may revolutionize the treatment of autoimmune disease.  And this has required incremental research built on a solid foundation of curiosity-driven basic research.  That’s the way science works.  There is much more is to come here, probably from elsewhere from the perspectives of Drs. Brumkow and Ramsdell in Seattle and San Francisco.

Part the Fifth: Not Blue, Not Red, I’m a Working Class Independent.  Les Leopold on the “Rust Belt” Survey:

Would you support a new organization, the Independent Workers Political Association, that would support working-class issues independent of both the Democratic and Republican parties. It would run and support independent political candidates committed to a platform that included the following:

• Stop big companies that receive tax dollars from laying off workers who pay taxes.
• Guarantee everyone who wants to work has a decent-paying job, and if the private sector can’t provide it, the government will
• Raise the minimum wage so every family can lead a decent life
• Stop drug company price-gouging and put price controls on food cartels

Michigan: 58.9%

Ohio: 58.1%

Pennsylvania: 56.8%

Wisconsin: 55.3%

For those politicians paying attention only to their donors, TINA is on life support whether you know it or not.  What comes after is still very much up in the air, though.

Part the Sixth Bonus of Sorts: Newton’s Third Law of Motion Applied to Our Diseased Politics.  The Third Law can be restated as, “For every action there is an equal and opposite reaction.”  Two current rabbit holes are worth exploring for those so inclined.

Here, the action is summarized by Matt Taibbi in James Comey Was Sure He Was Above The Law. Supporters Hope He’s Right.  The predicate was what has come to be known as “Russiagate” during the frenzy to explain the inexplicable (to the Professional Managerial Class) after the Tuesday following the first Monday in November 2016.

The reaction is described in an article in The Conversation by Cassandra Burke Robinson, a law professor at Case Western: James Comey’s Indictment Is a Trademark Tactic of Authoritarians.  The other operative “law” here is ,“What goes around comes around,” which is a curiously difficult concept for our erstwhile political leaders of both sides.  These people are also similarly dense when it comes to the prophet Hosea’s most well-known saying: “For they have sown the wind, and they shall reap the whirlwind.”  But there you go.

See you next week!  And thank you all for your support!