From Mice to Medicine - Time to Stop Funding the Wrong Translation?

Prologue

It was an intense day. Between sessions, during the breaks, I began to notice something unusual. Many of the participants were strikingly young. Some looked like graduate students, others like high schoolers. But as the day unfolded, it became clear that these weren’t students. They were families. Parents who had spent the better part of a decade caring for children with Glut1 deficiency and rare epileptic syndromes.

And now, they were here with those children, now radiant teenagers, even young adults. Healthy. Clear-eyed. Laughing quietly in the hallway. They had outgrown their prognoses, not by chance, all on KD on and off, through the tireless efforts of the dietitians, clinicians, and researchers who had helped them navigate childhood, adolescence, and everything in between.

They were at the conference to say thank you. And they did, with calm dignity, to the professionals who had made the difference. Not just the ones who asked the hard scientific questions, but those who stayed with them through the unknowns. Those who listened, adjusted, responded. This was a room anchored in memory, humility, and hard-earned gratitude.

Almost everyone in that room was focused on the future of the ketogenic diet, on uncovering its mysteries, asking why it works, for whom, and in whom it has limits and why. The energy was not one of triumph, but of shared responsibility. A commitment to keep asking better questions.

In defense of relevance, of clinical outcomes, patient stories, and the many unanswered questions that still deserve human answers i write today.

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In 1937, John Steinbeck published Of Mice and Men, a title borrowed from a centuries-old Scottish poem by Robert Burns. The line “The best-laid schemes o’ mice an’ men / Gang aft agley” translates roughly to “The best-laid plans of mice and men often go awry.” Burns had written it after accidentally destroying a mouse’s nest while plowing a field, an image of unintended consequences, a metaphor of human plans undone by nature’s indifference.

Steinbeck saw in this a perfect metaphor for the fragility of dreams in Depression-era America. But the phrase has outlived its literary origins, it’s now a cultural shorthand for plans that fail despite our best intentions.

Which brings us to the present state of ketogenic diet (KD) research, and the misguided faith in mouse models that continues to dominate funding, and distort clinical priorities.

For decades, laboratories led by researchers have built elegant, grant-winning experiments using BTBR mice, Kcna1-null seizure models, and glioma-bearing rodents all in the service of elucidating mechanisms that, while fascinating, rarely clarify clinical care. These models often "work" in theory.  When translated into practice, their insights vanish under the weight of real human complexity, co-morbidities, diet adherence, genetics, polypharmacy, and socioeconomic barriers.

As Burns foresaw and Steinbeck understood, a nest built in theory is no match for the plow of reality.

So I must ask plainly is it time to stop funding endless studies from mice to men and start funding studies in humans, for humans?

If Steinbeck’s warning was about the fragility of human plans, then nowhere is that warning more appropriate than in the curated, hyper-controlled world of genetically engineered mouse models. These aren’t neutral tools of inquiry. They are architectural confirmations of bias designed, often unconsciously, not to test hypotheses, but to validate them.

For decades, NIH-funded research in epilepsy (same as Alzheimer) has leaned heavily on rodent models such as BTBR, Kcna1-null, and glioma-bearing mice to simulate complex neurological diseases. These models can illuminate a pathway, yes, but only in a vacuum. They offer clarity in control, not relevance in care.

Start with the BTBR mouse. In 2013, Ruskin and colleagues suggested that ketogenic diets improved core symptoms of autism in this model. But this mouse doesn’t even have epilepsy. No spontaneous seizures, no abnormal EEGs. Yet its use persists in the context of antiepileptic research. Why? Because the BTBR mouse is behaviorally abnormal by design. It was built to be broken.

When a dietary intervention like KD is applied and researchers see “improvement,” it’s tempting to infer causality. But what if what we’re seeing is not a correction of pathology but a rescue of an artificially induced behavioral extreme?

Moreover, the intervention window was only three weeks. Human ketogenic diets often span years. Add to that the genetic monoculture of BTBR, a single, highly inbred strain, and the relevance to diverse human populations, particularly those with comorbid ASD and epilepsy, evaporates.

Later studies have tried to pin the BTBR response to shifts in gut microbiota, but again, the microbial ecology of lab mice bears little resemblance to the real-time human gut under dietary stress, social exposure, antibiotic use, and cultural variation.Specifically, microbiota mechanism, while fashionable, is especially vulnerable to over-interpretation in mouse studies.

Then there's the Kcna1-null mouse, a genetically engineered model that lacks the Kv1.1 potassium channel subunit and is thus guaranteed to experience fatal seizures within weeks of life. In 2016, Simeone et al. found that KD delayed seizure onset and extended lifespan in this model.

 But what exactly does that mean?

This is not a model of human epilepsy, it's a study in engineered fragility. The deletion of Kv1.1 is not a common human pathology. And when the organism is built to die by day 43, pushing that endpoint to day 55 becomes, at best, a curiosity. It is not seizure freedom. It is not cognitive preservation. It is not a childhood spared from pharmacological polytherapy. It is, once again, an intervention solving a problem it helped design.

The glioma models follow a similar trajectory. Tumor-bearing rodents, most often injected with GL261 cell lines, are used to explore how KD alters tumor metabolism, how it shifts glucose dependency, modifies oxidative stress, or reduces tumor volume.

But the clinical significance is again elusive. These tumors don’t replicate the microenvironment, immune profile, or vascular complexity of human glioblastoma. Nor do their endpoints offer translational traction.

Tumor shrinkage is not survival. ROS modulation is not a meaningful improvement in quality of life. Worse still, the metabolism of murine tumors how they use fats, ketones, and glucose  differs in fundamental ways from their human counterparts.

Across all these models, the pattern is consistent, the closer the system is to engineered precision, the further it drifts from clinical relevance.

The biases are not incidental. They’re built in. Mouse models are often hypothesis-conforming by design. (https://www.linkedin.com/feed/update/urn:li:ugcPost:7314245588600934400/) A specific mutation is targeted, a predictable phenotype is induced, and the intervention is tailored to counteract it. Results, unsurprisingly, appear promising. And once a lab has built its reputation and its NIH grant pipeline around a particular model, the next study is rarely a challenge to its assumptions. It is a refinement.

The environment itself is sterilized, diet, light, temperature, stressors, all standardized to avoid noise. But human beings are noise. Our diseases are chaotic. Our compliance is irregular. The very data we care about, seizure control, relapse risk, long-term cognitive preservation, emerge only under the uncontrolled complexity of real life.

And the numbers don't help. Most of these studies are based on groups of fewer than 10 mice per condition. Strain-specific effects and idiosyncrasies become indistinguishable from generalizable outcomes. Behavior is interpreted as biology. And confirmation bias becomes indistinguishable from discovery.

This is not a case against animal models categorically. It’s a case against their overuse, overreach, and the illusion of generalizability they afford. Especially in ketogenic diet research, where a century of clinical experience already provides a human dataset that is being ignored in favor of mechanistic theater.

“If you build the mouse to be broken,” the saying goes, “any therapy can look like a fix.”

And that is precisely what we see across these models, surrogate endpoints masquerading as clinical breakthroughs. Liver-based mitochondrial shifts passed off as neural repair. Circadian rhythm normalization offered as seizure control. Volume changes in tumors treated like survival curves.

But children with epilepsy don’t live in cages. They live in families, schools, and systems. And what they need is not another abstract signaling cascade explained in a conference hall but an answer to the simplest question, does this diet work for me?

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Now imagine an established academic researcher makes this comment “Fasting is protective… ketones create more ATP than glucose… there you have it. If that’s a sufficient explanation, take a short nap.”

It is said with a smile. The audience chuckles. But the message embedded in that offhand line was not trivial. It was a casual dismissal of one of the most clinically grounded, biochemically plausible, and empirically supported mechanisms in the field, metabolic efficiency. It is too clean. Too elegant. Too measurable.

But instead the public got a cascade of rhetorical maneuvers, a series of polished, high-IQ dodges that obscured rather than illuminated the clinical reality of ketogenic therapy. In each case, what appeared to be intellectual nuance was in fact the architecture of avoidance, a refusal to let clinical clarity take precedence over mechanistic speculation.

So let’s walk through them, not as soundbites, but as symptoms of a broader institutional pathology.

 “I want you to pay attention to other substrates, not just ketones.”

The premise seems balanced. But in practice, this is a re-centering of the narrative, one that subtly demotes ketones from their well-documented centrality in favor of newer, less-tested signaling theories that mirror personal research interests like fatty acids, decanoic acid etc.

Ketones can be measured, sure in the blood not in the brain, but we see the clinical response don't we? Their relationship with seizure control is observable. They’re messy, yes, but falsifiable. And that’s precisely the problem for labs invested in complexity, once something is falsifiable, it can be proven wrong. But fatty acids, secondary metabolites, or hypothetical substrates? They exist in a gray zone always suggestive, never accountable.

So let us all ask, when does this kind of framing sacrifice objectivity? When does it become strategic? And is it nothing but the language of a researcher moving the spotlight away from what patients and clinicians can track and toward what only his lab can define?

What does invoking the imperfect relationship between BHB and antiseizure effect mean?

Blood pressure is an imperfect proxy for stroke risk. A1C is an imperfect marker for diabetic progression. Lithium levels don’t guarantee mood stability. Yet in every case, clinicians rely on these imperfect metrics because they work well enough to guide care. When can we argue that BHB is limited? Because it doesn’t satisfy an academic standard of perfection? Are we dismissing clinical utility in the pursuit of mechanistic elegance?

It is true and frustrating, we lack long-term data in humans because the field and ambitious IVY research labs have spent two decades chasing mechanistic mice instead of clinical outcomes.

The NIH has funded rodent model after rodent model. SUDEP in Kv1.1-null mice. Tumor volume in glioma lines. Microbiota changes in BTBR strains. But where are the 5-year follow-ups on children who discontinued the KD? Where are the biomarker studies that map BHB levels to seizure recurrence?

We funded metabolic signalers instead of metabolic success stories. And invoking multi-omic fishing expeditions in the same breath is a scary proposition of associations blinding the truth and murking the waters.

Yes, clearly I have mixed feelings about someone, who mocked the ATP hypothesis. Looking straight at the gazing radiant faces of the teenagers KD had helped.

For me the smirk wasn’t personal. It was epistemological.

We do not need more mouse models. We need more longitudinal cohorts. We do not need dietary theory. We need clinical discharge. And we do not need permission to take a nap. We need to wake up and dismiss those who have forgotten their first steps were at the bedside along patients.

In 2012 a study by Arnold et al. published in JCI tying brain insulin resistance to Alzheimer’s revolutionized the Alzheimer world, followed by the 2014 mouse model studies celebrated for revealing a molecular world of IGF‑1 resistance, IRS‑1 dysregulation, synapto dendritic damage. They offered promises of biomarkers, novel drug pathways, the possibility that Alzheimer’s might be metabolically treatable.

But the narrative around them also reveals how eagerly science can elevate mechanism over meaning. Because even while these papers were influential, critical voices emerged, questions about Westernblot image integrity that was the very scaffold these papers were build on crumbled, as Charles Piller describes in great depth and detail in his fantastic book "Doctored: Fraud, arrogance and Tragedy". Questions linger reproducibility about whether molecular signatures translate into human outcomes and what happens when all is rooted in fake images. Gone inside a rabbit hole are millions of NIH dollars, and over 15 years of effort. And yet funding, labs, prestige followed. The mechanism, persisted in some circles, created its own gravitational pull drawing in resources and creating a paradigm difficult to escape.

If key mechanistic claims as Charles Piller showed in his book relied in part on compromised data, academic ambition, and institutional blindness, then the mechanism-first model has even more reason to be questioned. For Alzheimer, epilepsy and KD use alike.

Because in science, what cannot be reliably reproduced in humans cannot serve as a foundation. That’s not merely a tragedy of misallocated funding. It is an epistemological crisis.

When Eric Verdin, president of the Buck Institute, states without irony that he is comfortable selling oral Ketone supplements tested and found safe(!) only in mice directly to humans, via Amazon, no less, because “human trials take too long” and people “have a right to try,” he is not accelerating innovation. He is dismantling the ethical architecture of translational science that earned him his academic stature in the first place. (full interview here https://www.youtube.com/watch?v=9G9QPdFehrE&t=203s)

Verdin's postulate is a violation of the very principle of controlled inquiry. The defense of urgency is not a substitute for the duty of reproducibility.

Verdin goes further. He explains that for a molecule like BHB for instance to become profitable, ie be patented, it must be “combined with something else” for instance maybe the decanoic acid mentioned earlier in this paper, in order to qualify for patent protection. The regulatory hurdles imposed on pharmaceutical companies, he argues, are too burdensome; they slow down progress. If a compound appears safe and the evidence in animal models is “strong,” then he is comfortable offering it to the public for unrestricted consumption.

Let us not be fooled by this pitch, is not a rational case for compassionate use. It is a commercial reframing of convenience as virtue dressed in the language of public access.

But this raises a deeper question, who benefits when the lines between preclinical speculation and human therapy are erased? If that’s the stance of a leading figure in the aging and metabolism world, then what exactly is Nestle doing, mentioned repeatedly in conflicts of interest across the ketogenic diet literature?

Bypassing pharmaceutical scrutiny? Marketing ketones-in-a-bottle directly to consumers? Or working quietly to secure provisional patents on naturally occurring metabolic intermediates perhaps the next “longevity molecule” found in something as unremarkable as rainwater, but repackaged just enough to be novel? Once mechanistic enthusiasm becomes monetized storytelling, the peer review process is no longer protecting patients, instead it is enabling narratives to masquerade as truth at the cost of patient time.

Because when speculation meets salesmanship, what reaches the public is no longer science. It is branding. It is biotech theater. And it carries the imprimatur of institutions who once prided themselves on asking the right questions now pivoting instead to selling the right answers.

The public doesn’t need faster access to untested hope. It needs slower, deeper truth from data that survives human time and human scrutiny. That’s not what the adolescents and parents in the Berlioz conference room today, who lived the data with their bodies, not in mice deserve.

Because in the Verdin paradigm, when what matters is the story not the outcome, a mocking comment about ATP becomes more persuasive than seizure freedom in a patient.

As a clinician, I find the drift dangerous.

It moves us toward a world, where mouse model explanation replaces evidence, and where complexity is used not to clarify, but to deflect, becoming mechanism without medicine.

At which point should we interrupt the mouse spun narrative and ask why chase every molecule when one metabolite, BHB, tracks with clinical benefit in children who are seizure-free?

And if we simply chart the epidemiology and remind the room that long-term outcomes aren’t missing because the diet doesn’t work, but because the funding was diverted to signaling studies in mice who never had epilepsy to begin with…They would both return us to a central point, that the ketogenic diet deserves to be deployed, studied in real world cohorts, studied in humans, and respected as the clinically effective therapy it has proven to be.

To quote Burns, through Steinbeck: “The best-laid schemes of mice and men gang aft agley. And perhaps no better phrase describes what happens when NIH funding, scientific careers, and mechanistic temptation conspire to move us further from patient outcomes in the name of elegant pathways.

What started as ketogenic therapy, a real, working intervention, is now being pulled apart by complexity, lab mice, and metabolic digressions dressed in prestige. And unless that changes, the science will keep working harder to explain less.

Humans are equipped with ancient adaptive mechanisms to survive fasting and starvation, mechanisms that trigger the metabolic switch and ketone production. The ketogenic diet doesn’t invent this biology; it leverages it. And the clinical evidence is now beyond doubt, the ketogenic diet is disease-modifying. Let us put that to rest.

So when a patient fails to respond, the question is not whether the therapy works. The question is what part of the adaptive machinery is blocked? Is it a gene polymorphism? A signaling defect? A failure in metabolic switching? These are not reasons to discard the therapy they are invitations to study the exception and learn how to help.

In this context, the work presented on lysosomal salvage pathways is not just novel, it is visionary. The idea that some patients may fail to mount a therapeutic response because of defects in intracellular recycling is rooted in elegant, evolutionarily conserved biology.

Even more compelling is the application: the intravenous infusion of fucose in GLUT1 deficient patients, bypassing the blocked glucose transport and enhancing lysosomal salvage. This is not theoretical, this is a direct, disease-modifying intervention. It shows that when you understand where the adaptive pathway breaks down, you can restore the signal.

From fasting, to autophagy, to lysosomal salvage this is the therapeutic arc. This is precision medicine done right. And these are the kinds of mechanisms we must explore not as academic detours, but as practical, patient-centered tools.

Because the children and families in the room are not here to debate theory. They are here because the diet worked. And when it doesn’t, they’re asking us to find out why, so it might work for someone else.

The solution isn’t another mouse. It’s accountability, falsifiability, and patients first.

Is it time to stop funding mice to men and start funding humans, for humans.

Author's Note As always, the views here are entirely my own — not those of my employer or former colleagues. This space exists to explore ideas, question norms, and sometimes make people just uncomfortable enough to think. If you’ve found your way here, you’re likely seeking what’s been lost in translation: integrity, systems-thinking, and a grounded view of the body as shaped by constraint, not limitless potential.

© [Arina Cadariu] [2025]. All rights reserved. This article is part of The Science of Letting Go—a personal and educational project exploring the intersections of biology, genetics, epigenetics, clinical medicine, epidemiology, and the ethics of scientific communication. All views expressed are solely those of the author and do not represent the views of any employer, institution, or affiliated entity.

This work is protected under international copyright law. No part of this publication may be reproduced, excerpted, copied, or adapted—whether in full or in part—without prior written permission from the author. Unauthorized use, including commercial or institutional repurposing by clinics, wellness providers, or longevity brands, is expressly prohibited.

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