Coffee Break: Advances in Limb Regeneration & Malaria, Plus Science & Politics and a World through the Lens of Tuberculosis

Part the First. Old Experimental Models in Biology Lead to New Knowledge.  Developmental Biology began as Embryology.  A few of us still kicking remember the transition and miss the holistic approach required to master the material.  Early embryological models included sea urchins and salamanders, tadpoles and the chicken.  Much useful research was done with these creatures.  But even in the beginning, none other than Thomas Hunt Morgan ditched embryology because he sensed that unless genetics was understood first, embryology would remain descriptive at best.  This was not necessarily so, but “descriptive,” along with “incremental,” was and remains unwelcome adjectives among some biologists, especially those reviewers who are deciding on the funding of their peers.  Thomas Hunt Morgan switched to the fruitfly Drosophila melanogaster, found the white mutation in his laboratory at Columbia University (ironic, given current politics).  What followed is modern genetics, including the discovery much later of the conserved genes responsible for animal pattern formation, also in Drosophila.

One “ancient” model system is the axolotl Ambystoma mexicanum (images of this adorable creature at the link; the axolotl is severely endangered in its native habitat in the Valley of Mexico, but various institutions maintain the species).  Limb regeneration has been studied in the axolotl for years.  A recent paper identified the developmental signaling pathway that produces “limb memory” necessary for regeneration of a severed hand.  This has been the question: How does the arm know how to (re)-build the attached hand?  Molecular basis of positional memory in limb regeneration (open access) provides an answer that will lead to further questions.  From the Abstract:

The amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signaling centers that together fuel regeneration…The molecular basis of positional memory and whether positional memory can be altered remain unknown.  Here, we identify a positive-feedback loop that is responsible for posterior identity in the limb of an axolotl (Ambystoma mexicanum). Posterior cells express residual Hand2 transcription factor from development, and this primes them to form a Shh signaling center after limb amputation.  During regeneration, Shh signaling is also upstream of Hand2 expression. After regeneration, Shh is shut down but Hand2 is sustained, safeguarding posterior memory…Our results implicate positive-feedback in the stability of positional memory and reveal that positional memory is reprogrammed more easily in one direction (anterior to posterior) than in the other.  Modifying positional memory in regenerative cells changes their signaling outputs, which has implications for tissue engineering.

Very technical, but no more so than bond market manipulation, which is way beyond my ken. This could be a landmark in developmental biology and the understanding of how tissues might be engineered in relevant clinical settings.  Does this mean the same circuitry is sufficient for regeneration of a human hand?  No.  But every little bit of knowledge helps, and dormant positional information may rest in our own limbs, waiting to be discovered.

Figure 1 is worth more than a thousand words. but there is another, more important, message embedded here: Basic research is the foundation upon which all clinical advances rest.  None of this research would have been possible without each of the following:

• 1-abc. The identification of animal patterning genes in flies and later in the one-vertebrate-is-as-good-as-another model organism, the zebrafish (I still have my copy of this issue). Hedgehog (Hh) is a founding family member here that includes sonic hedgehog (Shh).
• 1-c. Knowledge of molecular mechanisms of gene regulation that were identified first in bacteria and later in bacterial viruses (phages) and animal cells (loxP, Cre, Shh limb enhancer).
• 1-dehijkl. Research into how certain jellyfish and their relatives glow in the dark made possible the red, green, and blue colors (TFP, EGFP, mCherry) signifying gene expression in the living axolotl in real time.

Development of the techniques required for this research began more than seventy years ago, with one advance leading to another.  Yes, I can be a broken record on this, but biology is not simple engineering, and one never knows where, how, or when the next critical advance will be identified.  So, when people say that 50% cuts in research budgets and grant awards will have no effect because “most research is basically worthless” because of nothing other than “reasons,” they are completely wrongheaded.  Not to mention mistaken.  Please note that this is not to excuse any scientist for his or her misbehavior, recent or otherwise, but that is a different matter altogether and has been covered here in the past more than a few times.

Part the Second. A Victory in the Continuing Fight Against Malaria.  Malaria kills more than 500,000 people worldwide every year.  Most of these victims are children under the age of five.  Over the past twenty years mosquito nets treated with insecticides have been very effective at preventing disease.  However, the technique has diminishing returns because mosquitoes are adept at developing resistance to pesticides.  DDT was used to control mosquitoes in South Florida immediately after World War and DDT-resistant mosquitoes appeared by 1947.

A newly developed technique uses anti-malarial drugs to treat the nets.  These drugs then disable Plasmodium falciparum, which is responsible for ~90% of cases of malaria (and the deadliest form of five variants), by preventing the organism from developing in mosquitoes instead of treating people infected with the parasite after infection.  This research was published in Nature on 21 May 2025: In vivo screen of Plasmodium targets for mosquito-based malaria control (open access).  From the Abstract:

We performed an in vivo screen of compounds against the mosquito stages of Plasmodium falciparum development.  Of the 81 compounds tested, which spanned 28 distinct modes of action, 22 were active against early parasite stages in the mosquito midgut lumen, which in turn prevented establishment of infection…We generated several endochin-like quinolones (ELQs) that inhibited the P. falciparum cytochrome bc₁ complex…ELQ activity was fully preserved in insecticide-resistant mosquitoes, and parasites resistant to these compounds had impaired development at the mosquito stage.  These data demonstrate the promise of incorporating ELQ compounds into LLINs (long-lasting insecticide-treated nets) to counteract insecticide resistance and to reduce malaria transmission.

This is a necessarily technical way of saying the mosquitoes took up the drugs from the nets and the parasites were prevented from developing in the Anopheles mosquito gut because their energy metabolism was disrupted.  Thus, they could not migrate to the mosquito salivary gland and infect a human during a mosquito bite as the insect fed on the target’s blood.  A key is that even the insecticide-resistant parasites would not mature in mosquitoes exposed to the drugs in the sleeping nets.

The importance of these results is obvious: Prevent the parasite, especially one resistant to pesticides, from developing in the insect vector and it cannot infect the human host.  And just as obvious is that the entire world has an interest in focused mosquito control as the planet warms, and not only for malaria.  What is particularly interesting in the current political climate is this research was funded, by among other organizations, the following:

• Howard Hughes Medical Institute (Virginia)
• United States Department of Veterans Affairs through Veterans Health Administration, Office of Research and Development Program Award i01 BX003312 and VA Research Career Scientist Award 14S-RCS001
• National Institutes of Health Grant R01AI100569
• National Institutes of Health Grant R01AI141412
• US Department of Defense Peer Reviewed Medical Research Program PR181134
• National Institutes of Health SIG Grant S10 OD026929

We can note here that Plasmodium falciparum is not (yet) endemic in the United States.  Therefore, some of this US support must be filtering out to places like Equatorial Africa and South Asia.  As it should be, we must not forget.  No pathogen takes notice of international boundaries.  I do wonder, however, if any of these grants, some of which are longstanding (e.g., R01AI100569-11 is in its 11^th year), are on the very long cancellation list.

Part the Third. The John Birch Society Lives Still.  Those of us of a certain age remember the billboards when driving through the countryside: Get US Out! of the United Nations.  They were financed by the John Birch Society.  My favorite hamburger and milkshake stop on the journey to my university was papered with John Birch Society posters and literature.  This made for interesting reading.  But the JBS campaign against fluoridation of the public water supply was nonsense then and remains so.  Nevertheless:

This weekend, Robert F. Kennedy Jr. said that, if elected, President Donald Trump would work to remove fluoride from all public drinking water in the U.S. Trump has said that Kennedy, who endorsed the Republican after ending his independent White House bid, would play a major role in health policy if Trump wins. The crusade against that widespread public health policy is something that gained prominence back in the 1960s, due in part to one organization that elevated fringe theories.

The John Birch Society was started by a small group of wealthy businessmen, including Robert Welch and Fred Koch (father of Charles and David).  It expanded with chapters of likeminded Americans meeting in private living rooms and finished basements across the country, fueled by conspiracy theories that caused a schism in presidential politics. While the John Birch Society’s influence has waned, its impact is still felt today.

There is no evidence fluoride is harmful at the levels used, and contrary to General Jack D. Ripper it was not a monstrous Communist plot.  The evidence is clear.  Fluoride in drinking water prevents tooth decay:

As a dentist trained in India and a global health researcher based in the United States, I have observed the fluoride debate from a broader, global lens.  In many parts of the world, fluoride is not controversial – it is simply unavailable.  Millions suffer from preventable tooth decay because they lack access to fluoride, and therefore the protection it provides against oral disease.

In India, I treated patients who represented both extremes of the fluoride spectrum.  Some rural communities were exposed to naturally high fluoride levels, leading to debilitating skeletal fluorosis.  But in many urban and peri-urban settings, especially among low-income populations, fluoride exposure was virtually nonexistent.  The consequences were visible: advanced cavities in children as young as 6, chronic gum infections in adults, and widespread tooth loss among the elderly.

In these settings, fluoridated toothpaste was not always affordable or available.  Water systems were rarely fluoridated. The absence of fluoride was not a health preference — it was a systemic failure. My patients were not debating the merits of fluoridation. They were living with the consequences of its absence.

This duality shaped my understanding of fluoride not as a universal good or evil, but as a tool — one that must be managed carefully and distributed equitably.

Yes, and this tool must be made available to those who otherwise will lack it:

If fluoride is removed from public water systems, there must be a viable, equitable alternative, such as subsidized fluoride toothpaste, school-based varnish programs, or community dental sealant initiatives. Otherwise, the people most affected will be those least able to afford private care.

And with this we come to…

Part the Fourth: MAHA and What It Really Means.  When I first wrote about MAHA in a discussion of Casey Means MD and her book Good Energy: The Surprising Connection Between Metabolism and Limitless Health (2024), I was willing to suspend disbelief.  This was the week before Inauguration Day.  The long awaited MAHA Report has dropped, and we may defer to Dr. David Gorski’s review at Science-Based Medicine.  I asked in my discussion of Casey Means MD (the Surgeon General designee who did not finish her residency and is currently lacking an active medical license) and her book if MAHA was a trope or a movement.  I hoped for a movement.  Alas, trope is what we have.  This became clear in the latter part of her book.  Casey Means MD intends her approach to MAHA to be for only those who can afford it.  MAHA writ large is no different.  This is frankly a tragedy.

MAHA can be accomplished, but only by fighting Big Business, Big Ag, Big Food, and Big Pharma, so that (1) real food (instead of commodity crops) is grown and then eaten by everyone, (2) because food deserts are eliminated (one of which begins a few blocks from my downtown house), and (3) all who want one will have a job at a living wage.  If America is really the “greatest country in the history of the world,” these are not objectively difficult tasks.

Anyway, the current Secretary of Health and Human Services has confirmed that MAHA is little more than an excuse for, well, rich people to look down on their perceived inferiors with their Soft Eugenics, which can be described in Lambert’s Two Simple Rules of Neoliberalism: Because Markets, Go Die.  Only those who deserve it get sick and by getting sick they are letting the economy down.  RFKJr and his cohort really seem to believe that everyone grew up romping on the lawns of Hickory Hill when not sailing from Hyannis Port to the Vineyard while summering at the Compound on the Cape.  All this, of course, while never having a care in the world about diet, healthcare, money, education, or a fulfilling future.

Part the Fifth. Everything Is Tuberculosis, a Review Here So I Don’t Have to Do It as Planned.  Which is a bit disappointing, but when a scientist is scooped, he moves on or drives herself crazy.  We return to Science-Based Medicine again, where we find an excellent review by Scott Gavura of Everything is Tuberculosis: The History and Persistence of our Deadliest Infection by John Green.  The book is very good.  The review is to the point and includes a few quotations from the author that bring home our message for today:

Nothing is so privileged as thinking history belongs to the past.

Framing illness as even involving morality seems to me a mistake, because of course cancer does not give a shit whether you are a good person.  Biology has no moral compass.  It does not punish the evil and reward the good.  It doesn’t even know about evil and good.  Stigma is a way of saying, “You deserved to have this happen,” but implied within the stigma is also, “And I don’t deserve it, so I don’t need to worry about it happening to me.”

What’s different now from 1804 or 1904 is that tuberculosis is curable, and has been since the mid-1950s. We know how to live in a world without tuberculosis. But we choose not to live in that world.

I have used tuberculosis in my teaching.  Preclinical medical students generally do not grasp that infectious diseases of all kinds are scourges, still, in many parts of the world.  And TB has not disappeared.  Personally, when I want to remind myself of things not done, I remember this: “When John Keats was my age, he had been dead from consumption for more than forty years (jpg).”

Finally, from the reviewer Scott Gavura:

Ultimately, this is a book about much more than tuberculosis.  It’s about how we understand and talk about disease, how we remember it, and what it means to live in a world where people would rather not be reminded of unpleasant thoughts or how society influences individual health outcomes.  For science advocates, Everything Is Tuberculosis offers a compelling example of how science communication can be effective: accurate, rigorous, empathetic and personal.  For everyone, Everything Is Tuberculosis will change how you look at the world.

Too many books, not enough time, but this is book very much worth the read.

From Memorial Day 2025, see you next week.