1 Boring Old Man

Thank you Mickey for posting the link to the article. Very much appreciated.

A cogent quote from the article: “Criteria such as number of publications, citations, prizes, and recognition are irrelevant as these are simply self-rewarding artifacts of the system.” One is reminded of Thomas Kuhn’s vivid description of exhausted paradigms: “(We have) finally created only a monster… that is failing in application to its own traditional problems.”

Ionnidis probably wrote the two most important articles of the last ten years.

One of my nerdier but I think useful hobbies is doing a cryptic crossword daily. These are different from regular crosswords because your success will be determined by the ability to think outside the box and other than literally, rather than by g, or general knowledge.

For example, eight letters, “growth on face must be sore”=MUST+ACHE=mustache

A typical crossword would be something like “hair above the upper lip”

If you lock into one way of thinking or literal thinking on a cryptic puzzle, you’ll never get the answer. For example, if you think it must be some kind of tumor.

Research is more like a cryptic than regular crossword…what seems like the obvious way to solve the problem usually doesn’t work.

It sort of made sense that sequencing the genome would lead to a lot of breakthroughs, but it hasn’t happened.

This is one reason I was appalled at the arrogance of state-funded stem cell research (I have no religious dog in the fight). Because they were promising people results that they couldn’t guarantee.

Cryptic crosswords are also a great way to fight the loss of fluid intelligence that naturally declines with age. Maybe they should be required in research departments.

https://en.wikipedia.org/wiki/Fluid_and_crystallized_intelligence

This is from the 1999 Collins article he cited:

“The recent discovery of an altered gene (HFE) that leads to hereditary hemochromatosis,16 a common disorder of iron metabolism, provides an interesting example of the potential for using information about mutations to prevent an adult-onset disease phenotype. A recessive condition, hereditary hemochromatosis affects about 1 in 300 persons of northern European descent and is easily treatable if diagnosed early. Its major symptoms — liver cirrhosis, heart failure, diabetes, arthritis, and other organ damage — do not occur until midlife and are easily misdiagnosed. Untreated, the disease causes early death, but treatment by phlebotomy to remove excess iron allows people with hereditary hemochromatosis to live a normal life span. A single substitution of the amino acid tyrosine for cysteine at codon 282 accounts for the majority of cases.17
At first glance, hereditary hemochromatosis seems to be an ideal target for public health approaches to the prevention of hereditary disease: the disorder is common, the number of disease-linked mutations in the gene are few, and effective treatment can minimize or eliminate the effects of the disease. But closer examination reveals a number of complexities that have so far militated against the rapid introduction of this genetic test as a tool for disease prevention.16 Because the penetrance of the altered HFE gene is reduced, especially in females, clinical signs can range from none that are detectable to severe organ damage from iron overload. At the moment, simple detection of the mutation does not predict the most likely clinical course. Before population testing for HFE mutations is considered, further research is needed to explain the variations in phenotype among mutation carriers and to correlate the genotype more closely with health outcomes.”

Postscript: the treatment is still the same 17 years later.

(By the way this disease is often underdiagnosed in middle-aged people who present with depression and generalized somatic symptoms.)

I may have posted about this before, but this reminds me a bit of the gene therapy segments I wrote during my ten-year tenure as lead writer for the New York Jerry Lewis telethon, from 1989 through 1999.

We did some great work– our greatest accomplishment was establishing a rule that guests in wheelchairs would make entrances like everyone else, and not be pre-set on stage like furniture. We had 11-year-old kids in wheelchairs anchoring hard news segments; stuff that the National show was too uptight to try.

But every year, it was the same. We would be pressured by the National show to interview doctors and scientists and highlight some breakthrough in gene therapy that was just around the corner. The scientists were very, very clear when I coached and pre-interviewed them: No, absolutely not. Gene therapy as a viable treatment for MD might be 40, 50 years away. It might not work at all. And then the haggling would begin– National would try to rewrite our questions and our script into a puff piece, and we would keep dragging it back into reality. Those were the good old days… in the end, the scientists and my team got the last word, and we never made any promises that were unlikely to be kept. At least not on my watch.

The JAMA articles are good and great thanks for highlighting them. Although, one is reminded of the turn of the century physicist who said around 1899 that all great ideas in physics have been discovered. The Joyner/Ioannidis article gave me the idea of “third paradigm.” One paradigm in medicine lasted from early history into the 1800s – medicine largely as hype and myth. The second paradigm rolls in the treatment of scurvy, Pasteur, the discoveries of insulin and penicillin, and so on, up to the present with renal dialysis, transplants, and more. The third paradigm (forecast by Joyner et al.) is what we will need when we are sitting in the midst of gigantic data mountains, huge inequalities in care, dilemmas like Alzheimer disease which seems a black hole for drug development. Something new has to be the third paradigm.