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Links to the 2 papers for those who don’t want to look back

Zemke et al in Science https://www.science.org/doi/10.1126/science.adt8307

Belk et al in Nature https://www.nature.com/articles/s41586-026-10939-0

It’s a major and fascinating discovery. We’re talking about a “hostile takeover” of blood monocyte cells that invade the brain and ultimately completely replace the brain microglia. The problem is these new microglia are pro-inflammatory.

A surprising finding is about CHIP (blood stem cells with mutations known as clonal hematopoiesis of indeterminate potential) that was shown to be protective. It’s surprising because CHIP is common with age and until now it has been linked to bad things such as cardiovascular disease, clotting, and cancer. If this pans out, it introduces the concept of immunotherapy of the blood (“brain immunotherapy”).

We discussed recent studies of microglia replacement and ways to keep our brain microglia intact, such as prevention any breakdown of the blood brain barrier.

The role of latent viruses and the mechanism of benefit of the Shingles vaccine were touched on.

Our conversation provides far more color and perspective about why their independent, complementary, and convergent findings are so important, debunking our longstanding belief that the microglia, the immune cells in the brain, are exclusively derived from the brain. Technology driven discovery. And what are the next steps in this line of research.

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Here are some of the points we discussed:

—The big market in healthy, well people. Tests, wearables, imaging, supplements, etc

—Algorithms feed the health anxiety in an amplifying, vicious loop on the social media platforms. When the algorithm knows you better than you.

—The special qualities of influencers, likable, relatable, vulnerable, appearance as friends, certainty, cultivating parasocial relationships. “I understand you, I see you, I hear you.” Often with financial conflicts of interest. Plus hidden financial benefits.

—The inverted pyramid of evidence and displacement of trust. Anecdotes believed and accepted as best evidence instead of rigorous randomized trials. A big flip, doctors losing trust to influencers and the sponsors of influencers.

—The Nocebo effect of harm through expectations

—The epidemic of neurologic tics during the pandemic traced back to TikTok, a viral contagion with 5.8 billion views (Figure made with Notebook LM)

—Potential for regulation of patient/consumers/prosumer influencers

—Celebrity influencers and the recent NEJM paper

—Many ideas for how we can mitigate this mess (Graphic by Notebook LM)

—Many illuminating patient examples: Femtech, silicon breast implant illness (BII), beta blocker experiment, a bogus bioresonance of hair test in a woman with GI symptoms, full-body MRI of brain lesions (transmitted to the patient by an automated message) that were a false positive.

—The term “wellness”

—Concierge physicians

Thank you , , , , , and hundreds of others for tuning into my live video with ! Join me for my next live video in the app.

Ground Truths has subscribers from every US state and 214 countries. There are over 302,000 followers of Ground Truths so nearly 90,000 folks who can easily convert to be free subscribers.

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A couple of other things to note:

—Thanks to the voluntary paid subscribers who support our summer internship program for high school, college, and grad school students. On August 6th, we had a poster session with our SRTI summer interns (pictured below) which was an extraordinary event with about 100 posters!

—I hit a publication milestone that I had not ever envisioned. More than 400,000 citations with an h-index of 259, as tallied by Google Scholar

Thanks to all for your support of Ground Truths.

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In this edition of Ground Truths I will go through the completely revamped understanding for what happens to our brain as we age from recent breakthrough studies.

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A Major Inflection around Age 50

From donor postmortem brains studies in people ranging from age 20 to 100 years, Zemke and colleagues in Science demonstrated the midlife inflection in the hippocampus tissue via multiple omics: gene expression, methylation, chromatin access, and 3D chromosomal architecture. You can easily appreciate the sudden shift in the Figure below (this and the other Figures made with the help of Gemini Notebook) characterized by cytokine production (inflammation) and an energy crisis for astrocyte mitochondria, starving for fuel because of impaired ATP synthesis. This was not what was expected: that with aging astrocyte cells would display senescent markers (“zombie cells”). They were nowhere to be found.

The Invasion, A Hostile Takeover

As astrocytes, the cells responsible for housekeeping and brain security functions, undergo attrition, the blood brain barrier loses its integrity and enables an invasion of monocytes from the blood. The original brain microglia (Micro1) are replaced by transformed monocytes (Micro 2) that are highly inflammatory. As soon as they take residence in the brain, they change their identity to microglial.

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The recent paper by Zemke and colleagues was fully replicated and extended by Belk et al proving the source of the Micro 2 cells—from the blood monocytes, derived from the bone marrow. And this replacement began in midlife. The two groups proved that via different tracking techniques. Zemke used the 4-way multiomic approach (summarized above), particularly methylation (single-nucleus methyl-3C sequencing, snm3C-sequencing), to define the origin of the replaced microglia, whereas Belk’s group used somatic mutations of the cells to identify their lineage (what they called Passenger Assisted Clone Tracking or PACT). This is completely opposed to what had been believed, with the blood brain barrier expected to prevent a massive infiltration of peripheral immune blood cells. Previously, studies using just gene expression could not differentiate the 2 origins of the microglia, which can be considered the “transcriptomic illusion". RNA-seq just scratches the surface. It took single-cell and multiomics to get this straight. Three other points were notable: (1) it’s a unique feature in humans, not seen even in non-human primates, (2) the process of replacement is more aggressive in men compared with women, and (3) the Belk study demonstrated the replacement in other regions beyond the hippocampus, such as the cerebellum and pre-frontal cortex.

Another new preprint study of the microglia derived from peripheral monocytes (produced in the bone marrow) identified the brain-meningeal reservoir for the incoming migration of cells.

Back to the hippocampal astrocytes, in contrast to the speed of monocyte invasion, they are dying off at a slow rate via lysosomal autophagy (waste clearance), about 0.2% per year in a steady pattern from age 20, as tracked by methylation.

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Then What Happens

The epigenetic approach (Zemke et al) gets us to 3D architecture thinking to explain the pro-inflammatory process unleashed properties of the Micro 2 cells. With the change in 3D folding, a weakened genome organization, there is new contact between gene components that were previously operated by tens of thousands of base pairs. As shown below for Micro2, the looped DNA sets up interleukin-15’s promoter and enhancer elements to be in contact, and the result of massive release of cytokines

On the other hand, the genetic approach (Belk et al) unraveled how these peripheral immune blood cells could be protective of Alzheimer’s. I’ve written a lot in Ground Truths about clonal hematopoiesis of indeterminate potential (CHIP): here and here . These mutations of blood stem cells are generally thought to be harmful, associated with an increased risk of cardiovascular diseases, clotting, and some cancers. But when CHIP clones were in the brain microglia, there was the paradoxical salutary impact of a marked increase in clearance of amyloid plaques and ~50% reduction of Alzheimer’s disease and related neuropathology changes (ADNC). That reduction was even more pronounced with certain CHIP mutations.

The impact of somatic mutations in brain microglia has also come up in 2 recent studies. In Nature, this week the group led by Lee and colleagues identified a subtype of brain microglia immune cells that become more abundant during progression to Alzheimer's disease, trying to protect the brain. That came from extensive work from over 1,600 brain donors, 830,000 immune cell transcriptomes, and experimental models. Another study in Cell, by Huang et al, reported somatic mutations in microglia cells were markedly pro-inflammatory. Their finding of CHIP over-represented in these cells sits in opposition to the findings of Belke et al and awaits clarification.

The Implications

There are a couple points worth emphasizing in the challenging dogma department. The discoveries summarized here would not have been possible a few years ago. They required a stack of omics—both epigenetic and genomics—and 3D representation of the genome architecture, facilitated by machine learning of huge datasets. From this work we have a newfound appreciation of the physical folding of our chromosomes in each cell, and how the erosion of the genome 3D architecture leads to molecular chaos, serving as the basis of the brain cell changes. The results also back up the principal finding of proteomic organ clocks that human aging is not a linear process.

This work, in aggregate, has so many other important takeaways. We’d all like to keep our brain intact, avoid loss of memory and cognitive function. While many experimental animal model studies have suggested this might be achieved by microglia replacement, that’s an invasive procedure requiring infusion to the central nervous system of direct implantation to the brain, and of uncertain safety with no human data. In contrast, the ability to use peripheral blood cells, such as accessible via genome editing or immunotherapy, is a new potential path that has been introduced by the Micro 2 discovery. The organ and cell clock proteomic work has indicated that the brain and immune cell aging are the dominant factors correlated with maximal human healthspan and lifespan. Now, from these landmark studies, we’re seeing an unexpected coalescence, another dimension of the brain-immune axis, providing a novel concept for prevention of Alzheimer’s disease and slowing of brain aging. How we might in the future be able to block inflammation by preventing the massive infiltration of blood monocytes into the brain, is such a new and intriguing opportunity.

Please note I will be doing live Ground Truths with Julia Belk, (Substack @juliabelk) first author of one of the 2 main studies discussed here, on August 24th at 11:30 AM PT

Note: I wrote this essay. There was NO use of AI for any text. Help with making Figures as noted above.. I have no conflict of interest with this content.

A Quick Poll

Ground Truths has subscribers from every US state and 214 countries. There are over 302,000 followers of Ground Truths so nearly 90,000 folks who can easily convert to be free subscribers.

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A couple of other things to note:

—Thanks to the voluntary paid subscribers who support our summer internship program for high school, college, and grad school students. On August 6th, we had a poster session with our SRTI summer interns (pictured below) which was an extraordinary event with about 100 posters!

—I hit a publication milestone that I had not ever envisioned. More than 400,000 citations with an h-index of 259, as tallied by Google Scholar

Thanks to all for your support of Ground Truths!

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Here are 20 temporal pattern signatures for the UK Biobank cohort, which help to provide the biologic mechanism of a person’s disease, as shown for multiple conditions like heart attack, breast cancer, and depression. That is, the same disease phenotype can link to different genomic pathway underpinnings. An example for breast cancer could be related to signature 8 or signature 7; the latter tied to inflammation and metabolic abnormalities. This biological pattern could also be used to detect likely medication failure (such as SSRI treatment for depression) and predict rare diseases.

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In fact, the model was used to discover genomic signatures for different diseases, as shown below.

This model predicted 1 and 10-year risk of diseases at the individual level and far surpassed routinely used clinical prediction calculators such as the pooled cohort equation (PCE) for coronary artery disease (0.89 vs 0.68, respectively, 1-year risk ) and the GAIL model for breast cancer (0.783 vs 0.54, respectively). ALADYNOULLI also surpassed accuracy for precision when compared with the recent Delphi-2M model that I wrote about here

The ALADYNOULLI paper is packed with information and equations and is not easy to get through without a sophisticated math background. That’s why the summary infographic below (made by Notebook LM) may be helpful to grasp its main findings

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Prediction of Your Health Trajectory in Context

The new model substantively adds to many other recent reports that include Delphi 2M, APOLLO, and AURORA that predict future health events up to 20 years out. Each of these models were different with respect to inputs, how patient data were represented (tokens, embeddings, or latent states), and prediction outputs as briefly summarized in the Table I made below. Notably, the inputs are complementary and likely additive, such that the deeper and longer (longitudinally) the data re for each individual, the better predictive accuracy will be possible.

Adding to these models are many specific disease prediction (e.g. cancer, asthma, diabetes, neurodegenerative diseases) and sources of data (such as sleep lab, wearables, or high-throughput proteomics).

We are now seeing intense efforts at medical forecasting which will continue to evolve and something that was not previously possible in patient care. What I mean is that we could provide a rough sense of a patient’s risk for, let’s say Alzhiemer’s disease, but could not temporally place when it might occur. Age 65 or 95? It makes a huge difference. And so does the ability to apply counterfactuals, what-if scenarios for the individuals to reduce the risk, markedly defer a condition’s appearance, or even fully prevent it. That’s why ALADYNOULLI adds yet another dimension, different methodology, multiple patient cohorts, and novel findings that further add to a new prediction and prevention dimension of medical practice. It couldn’t have been done with multimodal AI.

Note to readers: I wrote this post entirely. There was no AI used except to generate 3 Figures by Notebook LM (Figure 1,3 and 4) as noted. Figure 2 above is from the Supplemental information of the paper. I have no COI related to this post.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 61 summer interns here with us now! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths.

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“The future of biology is programmable.”

To give you a sense of how important this topic is, Patrick Hsu is the first guest we’ve had back to Ground Truths since the podcast began a few years ago. Nearly 2 years ago we spoke about digital biology but so much has happened since to help unravel the complexities in the language of life.

Patrick is a co-founder and core investigator at the Arc Institute. His work is at the intersection of biology, engineering, and AI. At the ripe old age of 33, he’s a pioneer of genome editing technologies and my go-to for tracking progress in digital biology. Besides that he’s a great explainer with frequent use of metaphors and simplification of very complicated stuff.

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Here’s what we discussed with the relevant links:

—Our recent review in Nature Biotechnology on the large language of life models (LLLMs). GBAI-generalist biological artificial intelligence

—The 2 multi-agent AI Nature papers in May for accelerating drug discovery: Full House (Robin) and Google Deep Mind (Co-Scientist) Multiple drug candidates were described as an outgrowth of multi-agent AI , with a 200-fold decrease in workflow time.

Below Figure from synthesis of the Robin and Co-Scientist papers: “AI devises hypotheses and ways to test them,” Nature News and Views, by Oliver Elemento

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—Biomni published in Science 9 July

An infographic by NotebookLM below helps give you a sense of what—a diversity of important tasks— accomplished by Biomni

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—New workbench offerings by the AI companies including Anthropic’s Claude Science, Open AI, Google DeepMind and the competition with academic spinoffs

—Spud Cells

—Virtual Cell project, which it’s such a big deal, and the importance of perturbations

—Alzheimer’s disease with OpenAI for finding mechanistic new targets for drug discovery

—The Nature Editorial

—Mid-Journey’s Ultrasound Imaging of the “Whole-Body” (and we’re not imaginative enough, the need to think big)

—Mitigating the worries about humans as lab assistants and nefarious use to produce bioweapons

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A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 61 summer interns here with us now! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths.

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The Chronological Illusion: Aging Isn’t Linear

It is well recognized that each of us age at a different pace, exemplified by person aged 90 who has never been sick and physically appears to be decades younger (what we’ve called the Wellderly or Super Agers). But the overall assumption has been that all of us undergo a gradual, steady, linear process of aging, predictable wear and tear throughout lifespan, as assessed via the calendar. That “chronological illusion” (the dotted line below) has now been debunked. Multiple studies that used large-scale proteomics (proteins or other omics/biological metrics and imaging) and have found 3 major waves of aging that occur around ages 34, 60 and 78 years, as shown below.

Simplified redraw of Figure 1 from the review which cited 7 studies, made with ChatGPT

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Aging Is Asynchronous in Our Body

It also turns out our organs age at a different pace. We might not have known that without the ability to do high-throughput proteomics with AI analytics. By that I mean being able to assess up to 11,000 proteins from a tube of blood and use AI to define which proteins are tracking which organ and the immune system. Perhaps the best way to prove this asynchronous process within our body is from the world’s oldest longitudinally followed birth cohort— the UK’s National Survey of Health and Development (NSHD). All of the 1,800 participants were born in the same week in 1946. At age 63, proteomics were assessed for 6 organs and the immune system. In the Figure below, you can see there is about a 10-year spread of organ and immune system pace of aging among the cohort. Conventional, top left, refers to whole body, that is all measurable age-related proteins without breakdown by organ.

Within participants there were differences in the chronological age compared the person’s organ age. In the example below, the heart shows accelerating aging. Multiple studies of organ clocks have correlated fast aging of an organ with a disease indexed to that organ, such as heart to heart failure or brain to Alzheimer’s disease.

This pattern of asynchronous organ-specific aging has been noted in several proteomic studies, and has been shown to correlate with lifestyle factors (such as alcohol intake and liver age) and as I previously reviewed in Ground Truths hormone replacement therapy and the immune system age. To give you a sense of the breadth of what organ clocks tracked in the NSHD cohort, from the paper: “The organ clocks were adversely affected by overweight in adolescence, lack of education, smoking and various types of adversity across the life course (such as parental divorce or lack of social support). In contrast, there were several healthspan-protective factors including normal birthweight, higher childhood socioeconomic status, sustained physical activity and moderate alcohol intake.”

Cell Clocks and the Master Regulators of Aging

Discovering organ clocks can be considered a breakthrough in their own right. But it goes deeper—to cell clocks. Frankly, I would not have expected we could track aging for different cell types, like brain astrocytes or microglia, from the proteins appearing in the blood. But that is what is now possible. This work was published just 2 weeks before our review and included in it. Over 40 cell types were assessed in over 60,000 individuals with over 7,000 proteins biological aging. About 1 in 4 participants had accelerated aging in 1 cell type. A compelling pattern was seen for many conditions, as illustrated below for brain astrocytes and the risk of Alzheimer’s disease (AD). People with accelerated aging (“old”) of these cells had a 12.6 fold higher rate of developing AD compared with slow (“young”) aging of astrocytes.

In a similar way to assess risk of young or old astrocytes, but now broken down by the known APOE4 risk allele, with 1 copy in the middle graph and 2 copies at the far right. You can see the minimal risk in the people without E4 (at left below, 2 copies of E3), risk of AD increased with old astrocytes in those with 1 E4 allele copy, but dramatically increased risk (nearly 40-fold) for old astrocytes vs young in people with 2 copies of the E4 allele. Noteworthy, the age of astrocytes predicted risk of Alzheimer’s independent of APOE4 status. It adds to p-tau217 and other neuroinflammation markers (p-tau181, NfL, GFAP) as a way to more precisely determine risk of Alzheimer’s disease. Put another way, simple people with APOE 4 are not at high risk for Alzheimer’s, but we didn’t have a way to know that before.

A consistent patten between organ and cell clock studies is that the more evidence for accelerated aging, reflected by more organs or cells, the more increased mortality during follow-up (or reduced survival), seen side-by side below for 2 cohorts (one showing mortality and the other survival).

The same pattern for aged cell types in the UK Biobank and relationship to survival is seen in the Figure below

The other key consistency is the prominence of the relationship of survival seen with 2 organ and cell types: the brain (neurons) and immune system (immune cells). When these exhibit normal paced aging, survival over 15-17 years approaches 100%. Accordingly, the brain and immune system have the appearance of master regulators of the aging process. They seem to be acting as systemic gatekeepers, supporting resilience despite extreme aging of other organs or cells. I’ve previously emphasized the interdependence of the brain and immune system. The brain can be viewed as “mission control” for the immune system.

It isn’t as if these organs and cell types are the only ones that are informative. That couldn’t be further from what has been seen. The aging of lung cells, smoking status, and the incidence of lung cancer, as shown below, is just another of many examples.

Impact on Routine Clinical Practice

We’re not there yet to implement organ and cell clocks, but not far away. I’ve had my organ clocks assessed by one of the companies in beta phase testing. Beyond more than 10 studies cited in the review, much more validation of organ and cell aging clocks is currently underway. This month we are launching a randomized controlled trial in participants with high-risk of Alzheimer’s disease testing aggressive lifestyle improvement with 24/7 coaching to prevent the disease. All individuals will have p-tau217 and brain clocks assessed at baseline and follow-up. The main endpoint is reduction in p-tau217 after one year, which has been shown to be particularly mutable in small intervention studies with exercise (previously reviewed in Ground Truths). All of the data thus far suggest that organ clocks are eminently mutable too, influenced by lifestyle factors, medications, and many other perturbations as reviewed above.

Let’s take a step back on how this field of aging has evolved. The concept of metrics to assess biological aging got its roots more than 15 years ago with the seminal work by Steve Horvath and others assessing DNA methylation (epigenetic) clocks. Here’s my conversation about epigenetic clocks with Steve Horvath. That first generation was built on with other information, be it from plasma proteins or clinical data, to yield more refined molecular clocks. But only in the past few years, have we seen the field move from assesing human aging more holistically to getting specificity at the organ and cell levels. The Table below from our review summarizes what can be considered 6 generations of biological clocks.

This progress has implications for the practice of medicine and the potential for achieving reversal of aging. Detecting accelerated aging of an organ could enable a new path to prevention. Take a person with risk factors for heart disease who exhibits accelerated aging of his artery clock and/or blood vessel cell clock; there’s potential for a new dimension of risk to be ascertained. There is no shortage of means to help prevent atherosclerotic heart disease for such individuals. Perhaps more striking is a new window into the aging of our immune system, for which we have no way to assess in the clinic today, but now could be quantified at both the immune system and immune cell levels. That could provide the advance warning for the need to amp up the immune response, be it by lifestyle factors, vaccines or medications. And don’t forget that the same clocks can be used to assess the impact of the preventive strategy or intervention. For the 2-stage prevention of neurodegenerative diseases, the data from clocks would be added to other layers of data to assess concordance and directionality (Figure below, abbreviations PRS-polygenic risk score, EHR-electronic health record, MCI-mild cognitive impairment).

I won’t go through all the organs (or 40 cell types) but I hope this gives you the sense of enabling precision prevention.

There is considerable investment and excitement about partial cellular reprogramming (also known as “rejuvenation”) and other biotech interventions to slow the human aging process. Last month cellular reprogramming (with 3 of the 4 Yamanaka transcription factors) was initiated in a pilot trial of patients with advanced eye diseases. While that may show aging of retinal cells is slowed, it still would not demonstrate our ability to slow or reverse human aging. But comprehensive organ and cell clock assessment may ultimately provide surrogate endpoints to support efficacy and pre-empt many years of clinical trial follow-up. That’s much further away than using clocks in the clinic, but a realistic possibility if validation for such an approach is achieved.

We have a problem right now with some aging clocks. They (mostly methylation, epigenetic) are being sold commercially direct-to-consumer without standardization or reliability, and at considerable expense. I would suggest not buying any of these tests. The tests with the most potential are at the organ and cellular level, and none are commercial at this point. That will change in the next year, but will still require attention to adequate validation and standardization, and the need to bring the cost way down, which is possible when done at scale. We’ve seen that at the UK Biobank, which was able to do 6,000 plasma proteins (O-link)for approximately 500,000 participants at ~$50 a pop (original charge for O-link and Somascan was >$900 for each individual).

Like so many other biomedical advances I have recently reviewed, we’re seeing the product of very large datasets and AI analytics. That was the case for the 14-protein blood test predicting and preventing lung cancer, the breakthrough blood test for assessing the tumor microenvironment, and use of imaging the thymus for immune system health Add organ and cell clocks to that quickly growing list.

I hope I haven’t lost you along the way, as this post was fully intended to be practical, a translation of our publication with high density information and the usual jargon that makes it hard to ingest, especially for folks not grounded in this stuff. For those who have been following Ground Truths for the past few years, you will recall how excited I was about the discovery of organ clocks back in late 2023. The field has gone forward at torrent pace since then, with the added dimension of cellular clocks.

The transition from calendar to clocks in medicine will take longer than it should. It requires a structural shift in how we define age. It doesn’t mean we abandon
chronological age, but counting candles is fixed and will be transcended. Biological age is now measurable at a granular level and increasingly shown to be modifiable. I believe this represents the most important advance we have yet seen in the science of human aging. It paves the way for a great inflection for promoting health and preventing diseases in the future.

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A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns here with us now! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths.

Recently, Professor Aaron Newman at Stanford and colleagues from many US leading centers published a landmark paper in Nature. It may ultimately be considered one of the most important leaps in cancer diagnostics in decades.

This was a massive undertaking involving 10 million single-cell RNAseq in 10 types of cancer to define 9 TME types by spatial omics which they called “spatial ecotypes”. It was AI-enabled by machine learning (Spatial Ecotyper from biopsy samples) and extrapolating that to knowledge to deep learning AI (Liquid Ecotyper from blood samples). The whole project took several years.

Here’s an infographic summary I made with the help of NotebookLM along with the Figures that follow.

Some of the key points from our conversation:

—TME is the soil in which the cancer cells live. It strongly influences whether the cancer cells will thrive or not, spread, respond to therapy, and determine the fate pf pre-cancerous lesion (as seen in recent important paper in pancreatic cancer evolution and colon cancer development).

—Ecotypes, a term coined in 1922, to get at the local environment of tissue and cancer, was repurposed in this new project. Good metaphor: neighborhoods. And emphasis on location , location, location like real estate.

—In the clinic today, the only window to TME is via a biopsy. But decisions for treatment are not based on TME, they are based on biomarkers like tumor mutation burden (TMB), PD-L1 levels , or volume of tumor DNA by liquid biopsy.

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—TME is dynamic and changes over time so a single snapshot won’t cut it.

—Spatial 3D maps of TME from 10 million cells, 10 cancer types led to 9 spatial ecotypes (with the Spatial Ecotyper machine learning). Validation across 3D grids (such as Visium) and multiple cohorts. The cell location base within TME is striking.

—These 9 neighborhoods are conserved and very different. SE4-immune system is asleep, hypoxic; SE 7/8 are “war zones” rich with immune cells, hot tumor; SE 5 exhibits intense immunosuppression, hostile vs immune system, portends poor survival, SE9 deep in core, driving angiogenesis (new blood vessels)

—Now rich information from these 9 SEs needs to be extrapolated to a holistic blood test of TME. It turns out an extension of tapping into methylation as used by some liquid biopsy cell-free DNA tests works very well, providing cell identity from the DNA fragments leaked into the blood. To get to TME spatial biology in a tube of blood. Akin to wastewater surveillance form municipals for detection of infectious disease pathogen sequence variants and circulating levels. A triumph of AI analytics made this possible!

—The Liquid Ecotyper was validated in 78 patients with malignant melanoma pre-treatment from Yale University. SE 7/8 benefited from immune checkpoint therapy; SE4 resisted treatment, shorter survival. Matched with tissue biopsy work.

—Work beyond publication ongoing in many types of lung cancer, bladder cancer, mesothelioma, and response to other therapies like CAR T and bispecific antibodies. This is critical since we have slew of different cancer immunotherapies (see my pyramid Ground Truths review) and we’re not sure who, when, how to use them to drive optimal cancer outcomes in patients. May also help predict other types of therapy (not just immunotherapy) for cancer.

—The blood test can performed serially which is a major advance compared with how we are currently “flying blind” and misled by imaging.

—Started a company Liquid Cell Dx to make the TME blood test commercially available. May be available sooner in the academic centers in the current study.

—The use of SEs may extend beyond cancer!

A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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“I may be the expert in cancer, but you are the expert in you.”—Elisa Port, MD

Dr. Elisa Port is Professor of Surgery, Icahn School of Medicine at Mount Sinai; Chief of Breast Surgery for the Mount Sinai Health System; Director of the Dubin Breast Center; and Director of the Center of Excellence for Breast Cancer at the Mount Sinai Tisch Cancer Center, a NCI-Designated Comprehensive Cancer Center. She is remarkably well qualified to provide guidance for prevention and treatment of breast cancer, and runs a model program at Mount Sinai in New York (←we’ll get into why I say that).

She has just published a terrific book that centers around the concept of informed optimism. Many of her patient stories are integrated.

We tried to cover the waterfront during our conversation including:

—4 Ws for reduction of risk: weight, walking, wine, and working out (especially in Nature, “green exercise”)

—Only 10-12% of women will ever develop breast cancer during their lives

—Role of adipocytes (fat cells), aka estrogen and inflammation factories

—Misinformation (underlying the need for this book)

—Pervasive myths of magic supplements, with safety issues of unregulated intravenous drips and others when analyzed turned out to be crushed up, dried house plants

—Total body MRI: mixed results from her patients

—Breast cancer on the rise in young women. Dr. Port relates about recent patients diagnosed in their 20s. Some without BRCA or other pathogenic mutation. Why?

—Mammograms in non-dense breasts pick up 80-90% of breast cancer. It’s the 40-50% women with dense breasts, which the scan is trying to find a polar bear in a snowstorm, is a problem. The problem with false-positives.

—Use of AI with mammography for increased initial detection, prevention, detect high-risk in women with a “normal” mammogram, and risk of heart disease (see my recent Ground Truths and piece in The Lancet on this important topic)

—Mount Sinai provides Transpara AI (the one validated by the big Sweden trial of >100,000 women) to all women getting mammograms FOR FREE. That is the best validated AI tool in medicine today!

—How a mammogram saved a patient’s life, not about breast cancer!

—Hormone replacement and birth control pills. How to assess benefit and risk in women young and older? Differences in the hormone risks.

—Tamoxifen for primary prevention in high-risk people. Reduction of breast cancer in 50% or more in these women. In some subgroups reduction as high as 80%!

—GLP-1 drugs may reduce breast cancer risk and this may not just be related to weight loss

—Lack of utilization of Genetic testing (it could be your father). I disagreed with respect to use of polygenic risk scores, as I wrote about in SUPER AGERS

—The lack of our ability to assess the immune system in the clinic and how that could change the face of prevention and very early detection of breast cancer

An infographic summary I made on Dr. Port’s book with the help of NotebookLM

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Note the Towards in the title of the 2 papers:

Summary of MIRA

This was designed to be embedded in a health system EHR to provide reasoning and action steps. There were 2 agents, the patient and the AI physician (MIRA). MIRA queried the patient’s history, the physical exam results, and could order labs, blood cultures, scans, medications, procedures, surgery, and triage for hospital admission. This was done in 500 emergency department established real cases with the MIRA results directly compared to 4 board-certified (BC) physicians, and also to a hybrid group of 2 BC physicians and 2 residents. (I won’t review the results of the hybrid group further since their performance in all tasks was lower than the 4 BC physicians.) It simulated the sequential way a patient’s data would be interrogated and processed. MIRA was enabled with 11 different tools and choices from >85,000 action options, operating in a standards-compliant framework for multi-step reasoning (using FHIR, ICD-10, RxNORM, ATC, LOINC, and SNOWMED-CT). The system was built on OpenAI’s GPT-4o.

The overall diagnostic accuracy for MIRA was 87.8% compared with BC physicians at 78.1%. That increase was especially notable for specific diagnoses like pancreatitis (95.2% vs 78.6%), and appendicitis (100% for MIRA, 88% for BC physicians). While MIRA ordered more blood tests (51% vs 28%), resource consumption was countered this by ordering substantially less scans. For therapy, MIRA surpassed the BC physicians 53.5% vs 38.3% for correctly ordering procedures such as laparoscopic appendectomy or cholecystectomy (Figure below). Other advantages for MIRA therapy included better IV fluid management and analgesic adherence to guidelines, and an overall 35% increased alignment of clinical guidelines compared with the BC physicians. Of 468 medications ordered by MIRA, 99.8% were correct for indication and safety (such as allergy, interactions, and kidney dosing). MIRA triaged more cases than physicians for hospital admission, which reflects lack of being economically driven.

Because the design of the system would allow leak of the case data to the AI, considerable effort was made to avoid premature information flow. That worked well, with 0 of 933 cases exhibiting any leak. 880 adversarial prompts were tested and the system held up well, as it did for stress-testing attempts at hacking, medico-legal threats, and other patient agent trickery. MIRA also assessed multiple patient perturbations including high anxiety, non-English speaking, paranoia, and diagnostic denial, without affecting its performance.

Summary of AMIE

This system had a very different design, with its focus on longitudinal assessment of outpatients, with the primary goal of developing first-rate management plans. Like MIRA, there were 2 agents used. The Dialogue Agent was conversational, interacting with the patient, representing fast, System 1 thinking (À la Danny Kahneman, using Gemini 1.5 Flash), and asynchronous to the Mx management agent, System 2, slow thinking that used long, context processing (even though it was quick). AMIE assessed 100 patients with 3 visits (each separated by ~2 days) spanning 5 different specialties. The results were compared with 21 BC primary care physicians. A noteworthy feature was the Ensemble Refinement which took 4 different treatment plans developed and came up with a consensus, mimicking a real medical treatment board, as is typically seen with cancer management. The massive >600 clinical guidelines were fully tokenized (not just parts of them) to provide the grounding and citations for management. This ensemble only took about 80 seconds to produce. Like MIRA, this was all text based, which was defended as necessary in AIME for the intent to maintain blinding. 30 physicians rated the performance of AIME outputs vs the 21 BC PCPs. Unlike MIRA, patient actors were used. The performance wheel below shows the differences for AIME vs the PCPs for 6 metrics, all leaning to AIME for being slightly or substantially better.

Overall, for management reasoning, AIME was non-inferior to the 21 PCPs. By the 3rd outpatient visit, the rating of AMIE’s management plan was 98% vs 81% of the PCPs. Preciseness of treatment was 95% vs 67%. Expert guidelines alignment was 100% vs 86%, respectively. So while the overall management was non-inferior, there were several ratings that favored AIME’s management.

A new benchmark for medication management was developed, called RxQA, built on 600 questions to board-certified pharmacists and the content from the UK and US formularies. AIME’s medication management outperfomed the PCPs for the correct medication, dose, duration, side-effects, and follow-up evaluation. This was found with the more difficult cases even when the PCPs were tested open-book (58% vs 48% in favor of AI).

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The Implications

The new studies raise the level of capabilities for medical AI from what has been previously studied, which were relatively narrow, mainly for support in making a diagnosis or answering questions on a medical exam or from a patient. MIRA took on autonomous agent end-to-end assessment and action plans for each patient presenting to an emergency department. AMIE was geared to provide longitudinal assessment across 3 outpatient visits. Both used only 2 agents, one interacting with the patient and the other to do the AI work.

There are many reasons to think these are preliminary findings that do not reflect the real world of medicine. Both MIRA and AMIE are text-only AI, meaning all the other things that are part of medicine, from the patient’s non-verbal communication and tone of voice to the review of actual medical images, were not included. The cases used in both studies were “clean,” complete data from established datasets. MIRA interactions were capped at 20 conversation turns. AIME used patient actors. There was nothing done that truly represents the practice of medicine, which is typically characterized by incomplete and conflicting data. The 3 outpatients visits in AIME were set up 2 days apart, hardly simulating how hard it is to get appointments with doctors! Likewise, only 5 specialties of medicine were addressed.

But there were some findings that can be viewed as filling in gaps of current medical care. Improving diagnostic accuracy in MIRA was clear, although the comparator group was very small, with only 4 board-certified physicians. Getting 100% correct diagnosis and ordering a laparoscopic procedure for appendicitis is impressive, as was the accuracy of the medications selected. The breadth of conditions in MIRA were limited (n=8) even though there was an array of diagnostic tests, procedures and surgeries as part of the management option mix. The lack of economic incentives in the practice of MIRA management is desirable and even resulted in less expansive scan tests ordered.

For AMIE, a big advantage was the longitudinal context across 3 clinic visits. Unlike real patients today, the Patient Dialogue Agent didn’t have to fill out forms. There was memory and efficiency (not what we see in US healthcare). That agent was set up to be empathetic and attentive which showed up in the patient preferences, a pretty big gradient favoring the AI.

Both of these medical AI models were remarkably precise with respect to sticking to guidelines or providing specific plans. For example, the PCP in the AMIE study wrote “give an antibiotic whereas the AI prescribed amoxicillin 500 mg orally, 3 tablets daily for 7 days, and wrote to check for a penicillin allergy.

But here is the rub. Guidelines in medicine are meant to apply to the vast majority of patients, without specific regards for needs, fears, prior patient experiences, cost, and many other factors. Much of present day guidelines are provided by “experts,” that is they represent opinions that are eminence-based, not evidence-based medicine. So this very tight, superior alignment of the AI with guidelines is not necessarily a good thing, with the claims of great “precision.” Frankly, over-adherence to guidelines may presage the loss of the art of medicine, not taking in the human factor of each patient, and the human-to-human bond that would be the foundation of the patient-doctor relationship.

Where is this headed? The large language models (LLMs) will keep getting better. In fact, the ones used in these 2 reports are already obsolete. In the agentic AI era, there could literally be hundreds of specialized agents, such as one for labs, one for scans, one for sensors, one for environmental exposures, one for genetics/genomics, and so on. Today, with these new papers, we are only seeing the rudimentary use of agents.

You can think of MIRA and AMIE as a major step forward within the constraints of a simulation, not real medicine. But the improvements in AI’s capabilities are coming fast, and it would not be surprising to see some of the benefits here extended to the actual practice of medicine. To prove that, we ideally will need randomized trials of 3 strategies to assess outcomes: (1) end-to-end medical AI ; (2) human clinicians only; and (3) combining both. That won’t happen soon since are still on a steep slope of model improvement and such a large trial would not be easy to get funded, no less executed. In the meantime, we’ve got new evidence for potential ways that generative AI will improve medical communication, diagnosis, and management.

NB This post was written by me, no AI. I have no COI related to the content of the post.

A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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In this post, I’ll take you through the findings and the ramifications that it has for preventing cancer in the future. It’s a massive amount of work, so I will not get into the abundant technical details, but instead hit the high points.

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Let’s first go back to the CANTOS trial that set this up.

Background on an Old Randomized Trial

Back in 2017, there was publication of CANTOS, a large randomized clinical trial that assessed an anti-inflammatory medication (canakinumab, an interleukin-1β antibody) in more than 10,000 participants with prior heart attack for reduction of subsequent cardiovascular events. While the results were not compelling for this cardiovascular indication (small benefit and a risk of fatal infections), there was an unexpected outcome of reduction of lung cancer and fatal lung cancer during 5 year follow-up, both with a dose-response (Figure below for lung cancer incidence). At the highest dose of the drug, there was nearly an 80% reduction of fatal lung cancer. But the number needed to treat (NNT) with the antibody to prevent 1 person’s lung cancer was >1,000, which reflects there wasn’t a way to know who would benefit from the drug. Wouldn’t it be great if we could understand this better and identify whose lung cancer could be prevented with the interleukin-1β antibody?

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The New Study

Probing the UK Biobank

The first step was to do high-throughput plasma proteomics in over 48,000 UK Biobank participants (schematic below). This cohort had nothing to do with the CANTOS trial.

This involved assessing nearly 3,000 different proteins from the blood (O-link, ThermoFisher) and using machine learning of the data along with age, history of smoking and lung disease, to find the proteins that predicted lung cancer. There were 14 proteins that fulfilled this objective. They had 4 major categories of function indicative of deep lung cell stress: inflammation, lung surfactant production, epithelial cell secretion, and matrix remodeling (more on the latter 2 categories later). The proteins were present on average 5.6 years before UK Biobank participants who developed lung cancer. These 14-proteins (Figure below with risk of lung cancer) were assessed in 8 different cohorts with either the same (O-link) high-throughput proteomic platform or with Somalogic. The proteins were also confirmed in a Taiwanese cohort (comprised of 81% women, 62% adenocarcinomas) of whom 93% never smoked. Prediction of lung cancer incorporating the 14-proteins outperformed 2 prior lung cancer models based on demographics and smoking history (known as LCRAT and LLVP3). The 14-protein signature was also found in some people with idiopathic pulmonary fibrosis and in chronic obstructive pulmonary disease.

Replication of the 14-protein signature in 8 different cohorts (known by their acronyms like ARIC, EPIC, CKB, etc.)

Probing the Biology

There were important results of the TRACERx clinical study (Tracking Cancer Evolution through therapy [Rx]) that had to be folded in to help identify the source of the 14-proteins. That study tracked lung cancer evolution and post-surgical results. There was no correlation of the 14-proteins with more advanced lung cancer (compared with early cancers) and no reduction of the protein signature after resection of the lung tumor. So, surprisingly the 14-proteins were not coming directly from the tumor cells. What was the source of these proteins?

The next steps were to introduce the EGFR mutation to 4 different types of lung epithelial cells (basal, club, neuroendocrine, and AT2) in the mouse model to develop lung adenocarcinomas, and subsequently to test the impact of air pollution (particulate matter exposure), the EGFR mutation, and the combination. Single-nucleus sequencing of ~37,000 cells helped to get at the gene expression for the epithelial progression to cancer. As these different types of lung epithelial cells converged to the pre-cancerous KAC state (stands for KRT8+ alveolar intermediate cells, K for keratin). Notably, the 14-proteins were not secreted; these cells had lost their identity with malignant transformation. The source turned out to be healthy, wild-type (cells without the mutation) bystander cells sensing stress from the precancerous process, the formation of the KAC state.

Particulate matter activated macrophages to release interleukin-1β to drive production of the 14-proteins. The combination of interleukin-1β from PM exposure and the KRAS mutation took this 14-protein production to the next level. This was confirmed in human lung organoids with exposure to interleukin-1β, incriminating this factor as key to pushing dormant mutant cells into cancer and driving the 14-protein release.

Circling Back to the CANTOS Intervention Trial

With proof of the pivotal role of interleukin-1β, it was time to go back to the CANTOS trial participants and see how the antibody to it correlated with the development of lung cancer. Within 2,325 participants in that trial, there was a more than doubling of risk of lung cancer in this who had the 14-protein signature (high-risk, top graph below). And the high-risk group were the people who drive marked benefit from the interleukin-1β antibody (camakinumab, graph below, bottom) with an approximate halving of risk of lung cancer. The number needed to treat to prevent one case of lung cancer partitioned by the 14-proteins went from 1500 in the low-risk group to 50 in the high-risk group.

Here is a diagram to pull all of the above together (made with help from Gemini)

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The Clinical Significance of this Work

We don’t have any protein biomarkers that are validated for primary prevention of cancer, although there are some used as markers to help in early detection like CA-125 (ovarian cancer), CA19-9 (pancreatic cancer) and CEA (carcinoembryonic antigen, gastrointestinal cancer). The new study takes us to an unprecedented position for identifying and thoroughly validating a 14-protein signature for lung cancer.

This work took advantage of new methods that have only become available in recent years. At the top of that was the use of high-throughput proteomics to assay ~3,000 plasma proteins and use of machine learning to nail the 14 significantly linked to lung cancer. That is akin to many recent studies that started with 6,000 to 11,000 proteins in the blood and used AI to partition these as organ clocks and cell clocks, tracking their pace of aging status. this comes down to pinpointing the small number of proteins in the blood that correlate with a clinical metric or outcome. In the current study, showing these same 14 proteins found in the UK Biobank were predictive of lung cancer in 8 additional cohorts and in non-smokers strongly reinforced this as a seminal finding.

But this body of work went on to dissect the mechanism of the 14 proteins and what accounted for their production, through 4 different types of lung epithelial cells, laborious mouse model work with knock-in EGFR mutations, and extending into the known environmental hit of particulate matter from air pollution, strongly associated with lung cancer. We would have assumed the 14-proteins were coming from the cancer cells, but they weren’t. They were, challenging dogma, an indirect siren emitted from healthy cells, sensing the stress in cells transitioning to a precancerous state. Plus the confirmation of a double hit—particulate matter and an EGFR mutation—that led to the highest production of the 14 proteins. Imagine if we could identify a group of proteins that were predictive of each cancer 5+ years in advance and understand precisely the basis of the protein cluster! That’s where this is ultimately headed. And we’re just talking about the biomarker here.

The other dimension of this landmark study stemmed from serendipity. CANTOS was a trial directed at reducing heart disease, a secondary prevention for people who already had a heart attack. But the researchers backed into the finding of reduced lung cancer and fatal lung cancer with the innate immunity intervention of blocking interleukin-1β. While interesting, there was no way to practically take that to the clinic with a number needed to treat (NNT) exceeding 1,000 (to prevent 1 lung cancer) and the hazard of the antibody for serious infections. But CANTOS took the 14-protein biomarker story to a new level, by testing whether the antibody would work in the high risk group. And it did, lowering the NNT to 50 (figure below, made with Claude) in the 20% of participants who had the biomarkers. That’s a remarkable low number of people needed to treat to prevent one deadly cancer.

Now this, of course, is retrospective. We don’t yet have a clinical trial to prove that lung cancer can be reduced by 50% with the 14-protein biomarkers and the antibody treatment. That is the next step along the way. If it is proven prospectively, that would cinch a “prevmed", what I call a prevention medicine, here for preventing cancer. But if it weren’t for CANTOS the hunt for the biomarker would not have likely proceeded, no less identifying a highly promising interception, a primary prevention for the most common form of cancer diagnosed globally. And if we didn’t have the UK Biobank resource with almost 50,000 participants who had high-throughput proteomics and >17-year follow up for outcomes, the 14-protein biomarkers would not have been found. Just think that now all 550,000 UK Biobank participants have had O-link plasma proteomics, greatly enriching this resource for finding biomarkers and candidate prevmeds for many other types of cancer. Both the large CANTOS trial of >10,000 participants and the UK Biobank played an instrumental role in enabling the new study, no less many other cohorts with proteomics and outcomes for independent replication. All of this highlights how critical it is to have such clinical resources to make such pivotal discoveries that can impact medical practice and the lives of so many patients whose cancer could be prevented.

The new proteomic based work that elevated the potential for preventing cancer is complementary to the vaccine approach that revs up the immune system in a person at high-risk. These 2 primary prevention strategies could be combined, and would have even greater effect than either along in high-risk people.

What we have in this new study and context is the beginning of a roadmap, a template, to achieve primary prevention of a common and all too frequently lethal cancer. Once we can accurately predict cancer 5+ years ahead, the era of primary prevention will go into high gear.

NB This post was written by me, no AI. As noted, 3 images were made with the help of AI. I have no COI related to the content of the post.

A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths.

Helen Pearson, PhD, is an award-winning biomedical journalist at Nature, named European Science Journalist of the Year in 2025. She teaches science writing at University College London. BEYOND BELIEF is her second, just published book. THE LIFE PROJECT was her first.

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The points we covered include:

—The evolution of evidence over 8 decades, moving from rationalism, expert opinion, hunches (eminence-based) to empiricism, evidence-based

—The enormous devastating adverse impact of Dr. Spock’s Baby and Child Care book from a single sentence change, leading to an epidemic of sudden infant death syndrome. And how it ultimately got corrected.

—The term evidence-based medicine was coined in 1991 at McMaster University

—Iain Chalmers, Archie Cochrane and the Cochrane Collaboration

“The scandalous failure of science to cumulate evidence scientifically”—Iain Chalmers

—Systematic reviews

—Natural experiments (such as with Shingles)

—Resistance to change

“Challenging a doctor’s conventional way of practice is like hitting him in the intellectual testicles”—Drummond Rennie, past JAMA editor

—Evidence-based practice (and not) in the Covid pandemic

—Recent examples of challenging dogma (kindly stones, thymus involution)

—AI and misinformation, false evidence

Thank you , , , , , and many others for tuning into my live video with ! Join me for my next live video in the app.

A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

If you found this interesting PLEASE share it!

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Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in throughGround Truths.

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But now we’re seeing an exponential rise in new ways, clinical trial results, and a rich pipeline to prevail over cancer via immunotherapies. It includes an extensive gobbledygook of acronyms like ADCs, BiTES, CAR-T, CAR-NK, TCEs, and TRiTES that needs to be broken down. The purpose of this edition of Ground Truths is to take stock of the progress that is being made and where we are headed. In short, we’ve come a long way!

The takeaway lesson is we can’t have enough in the armamentarium of ways to amp up the immune response to cancer. If we’re going to achieve long term success and cures, in many patients it will take more than 1 drug class within the immunotherapy umbrella, i.e. combinations to get us to the goal. Especially promising is the future use of the immune system to prevent cancer in people at high-risk.

Here’s an infographic summary I made with help from ChatGPT Images 2.0 which, from bottom up, guides the inventory.

And a Table to summarize the number of agents in each category that are FDA-approved or in the pipeline.

In this post, in order to stay on point, I won’t get into some important details for each type of immunotherapy, such as the serious side effects that can occur, like cytokine release syndrome and other sequelae from unleashing the immune system including immune-related colitis, myocarditis, lung toxicity, and hepatitis. Rather, the goal of this summary is to give you a sense of how the field is evolving and its future directions.

Before getting into each category, just to point out there are over 2,500 drugs and programs for cancer immunotherapy now!

At the Foundation: Impact of Immune Checkpoint Inhibitors (ICIs)

The extension of survival (vs placebo) for these drugs ranged from a couple of months to about a year and a half, with extensive variability between types of cancer, different baseline treatments, and between individuals. Overall, the most extensive data available for the PD-1 and PD-1 inhibitors is with Keytruda (pembrolizumab), which now has >40 FDA-approved indications and is the top selling oncology drug in the world. Yet incompleteness of impact of ICIs, with only short-term survival improvement, reflects resistance manifest or developed during therapy. As recently reported, short term fasting (16-hours) enhanced ICI effects in patients. But that doesn’t change the big picture of only partial effects of ICI for most patients. That’s why there’s a whole new crop of ICIs well into clinical testing (TIGIT, TIM-3, VISTA, B7-H3, BTLA, and more) which may help in combination to delay or prevent resistance. For example, the LAG-3 targeted drug was approved in 2022 in combination with a PD-1 inhibitor (nivolumab) for metastatic melanoma. But the ICIs, including the new ones and the combinations, were just the beginning of a superabundance of ways to leverage the immune response against cancer.

I put oncolytic virus treatment as a way to rev up the immune system just above that (Figure above), with less aggressive pursuit than ICIs or the others we we’ll subsequently review. The overall track record looks good for safety, with the virus penetrating and killing cancer cells, along with pushing the immune system to kick in. Its first US approval (T-VEC) was in 2015 vs unresectable melanoma, and there are many viral agents (←an excellent review) in clinical development but they require injection into the tumor.

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Antibody Drug Conjugates (ADCs)

As seen above, the antibody bound to drug gets in through the tumor microenvironment to bind to tumor proteins (antigens) on the cancer cell surface. Then the cancer cell killing payload is released.

The are over 15 ADCs approved with many new indications being pursued, as indicated in the Figure below and this outstanding new Cell review. There are now over 300 investigational ADCs in the pipeline. And combination of ADCs with ICIs, presumably additive or even synergistic because of their different mechanism of action, also has initial clinical trial experience.

Bispecific T-cell engagers (BiTES)

BiTEs use the antibodies to bridge a tumor cell surface antigen and a T cell (CD3 on the surface) that rapidly activates cancer cell killing. Schematic below from Dana Farber.

There are already 9 different BiTES approved by FDA for several types of blood (liquid) cancers (e.g. multiple myeloma, lymphoma) and uveal (eye) melanoma. There are well over 500 more BiTES in the pipeline! These include many different T cell surface proteins besides C3 and moving onto tri-specific antibodies (TRiTES). While off-the-shelf is an advantage, they rely on engaging functional, non-exhausted T cells. Like ADCs, they are being explored as combination therapy with ICIs and as pre-therapy for CAR-T to achieve tumor debulking. The 3 generations of the T cell engagers is shown below and reviewed here.

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The CAR and TILs Story

I have previously posted on engineering T cells at Ground Truths for cancer, and for its mirror image—autoimmune diseases. A review in April 2026 provides an excellent state-of-the -science for “adoptive” CAR, whereby T cells are isolated from the patient, expanded, engineered with a specific receptor target, and given back to the patient (autologous). The first approval for this cell therapy was in 2017 for blood cancers (e.g. pediatric leukemia) and the success has extended to multiple myeloma and lymphomas but solid cancers have proved to be a formidable challenge. That is attributed to difficulty for getting cells into the tumor and heterogeneity of the antigens within the tumor. Back in 2024. tumor infiltrating lymphocytes (TILs), which use unmodified tumor cells that target many antigens, were FDA approved for melanoma. There are extensive strategies evolving to achieve success in solid tumors, including use of natural killer (NK) cells instead of T cells, and more recently CAR-macrophage (←good review here), and different antigen targets (such as CD70) of engineered cells (Figure), innovative ways to avoid T cell exhaustion, setting up charging stations in the body, or secreting proteins to enhance antitumor action, some referring that concept to an “armored CAR. “ AI is being used to determine best ways to optimize CAR cell binding. Recently (reported April 30), the first use of a stem-cell memory (CAR T SCM) type of of long-lived immune cells given to 11 patients with refractory blood cancers, which achieved success in many. Adding to this work was the use of a cytokine fusion scaffold (interleukin 7, 15 and 21) to augment functionality of the CAR T SCM cells.

While all these tweaks are being pursued, the major anticipation is to move from ex vivo to in vivo—inside the body with allogenic, off-the-shelf CAR therapy. This would take out huge expense and weeks of delay, preempting the need for manufacturing individualized cells manufactured and returned to the patient. Instead better delivery systems (viral and mRNA-lipid nanoparticles) are required, and initial validation has been seen for this in patients with refractory multiple myeloma. The strategies are getting increasingly creative and sci-fi like. A recent cover article (Figure) depicts the use of red blood cells carrying mRNA-lipid nanoparticles (little blue spheres on the red blood cells) that home to the spleen and are phagocytosed (eaten, taken up) by white blood cells (large blue cells) to deliver CAR. None of the in vivo, off-the-shelf CAR have been FDA approved to date, but this strategy is expected to be the mainstay of cell therapy for cancer in the future.

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The Vaccines for Treatment and Prevention

There are 2 types of cancer vaccines categorized by their goal: treatment and prevention. Mounting experience has been seen for treating refractory cancers, as summarized in the Table below, with impressive results for many refractory cancers that include pancreatic, glioblastoma, renal and melanoma. Recently, individualized mRNA vaccines were also shown to induce durable T cell immunity for triple negative breast cancer.

Most of these are personalized neoantigens, that is vaccines developed from the patient’s tumor antigens, which takes about 2 months to produce, and often given in combination with an ICI, as seen below. Many use mRNA-nanoparticles for their delivery. Increasing attention to simplify this process is being given to using antigens that are not personalized, to allow for scaling of this approach with reset to timing and cost, along with other ways to rev up the immune system in the vaccine such as adjuvant enhancers. There’s also the concept advanced for putting such vaccines directly in the tumor.

The other category is known as interception vaccines, intended to be used in patients at high-risk hereditary cancers, such as with Lynch syndrome or BRCA mutations. A Phase 2 clinical trial for Lynch syndrome carriers with an off-the-shelf neoantigen vaccine (antigen derivation shown in schematic below) was published earlier this year, demonstrating a robust immune response in 45 participants, given in combination with an ICI. Such work is extending to individuals with BRCA 1/2 pathogenic mutations which could ultimately prevent the need for bilateral mastectomy and risk of other cancers. Beyond that, preclinical evidence for interception vaccines has just been demonstrated vs pancreatic cancer using KRAS as a target.

Where Do We Go From Here?

With about 8 different classes of cancer immunotherapies that are available or under investigation, this is evolving like the multiplicity of treatment choices we currently have for hypertension or Type 2 diabetes that have a double digit number of treatment classes. How are we going to choose the right therapy or combination to achieve best outcomes, reduce side effects and cost? When should immunotherapy be given as the first line of treatment instead of traditional chemotherapy? How reliable are biomarkers that are typically used— PD-L1, microsatellite instability high (MSI-H), mismatch repair deficiency (MMRd), and high tumor mutation burden (TMB)— in guiding therapy? Or mutations in STK11 and KEAP1 genes that may denote resistance to immune checkpoint inhibitors? Do we need to rely on toxic chemotherapy (or surgery or radiation) to de-bulk a cancer before these treatments are applied?

We are missing two fundamental assessments to be much smarter for directing these therapies. For one, we have no immunome in the clinic—a way to assess the functional status of a person’s immune system. I recently reviewed in Ground Truths the landmark papers on AI of the thymus gland. We can derive a thymus health score from a low resolution chest CT scan and this score informs response to immune checkpoint inhibitor therapy, as shown below. It was far better than the PD-L1 biomarker, which is traditionally used for predicting ICI response. Look how survival was influenced for low thymic health scores in the right hand panel below. For decades we have ignored the importance of the thymus in adults for promoting our immune system health, and now have a way to assess it.

There are other ways to assess a person’s immune system, such as a proteomic clock to see if it is outpacing chronological age, and specific proteomic immune cell clocks. These are not yet clinically available but they would fulfill a major unmet need and could help anticipate failure of monotherapy (e.g. using ICI alone or at all).

The other missing piece is our inability to non-invasively assess the tumor microenvironment (TME). The TME consists of tumor cells, matrix, stromal (supportive, framework including blood vessel) tissue and immune cells. If we knew what was the status of the immune cells in the TME of a patient’s cancer we’d have far more insight. For example, high cytotoxic killer cells (CD8+) in TME is a good sign, whereas high proportion of Treg cells is a poor prognosis sign. The goal of therapy is to change a “cold” tumor into a “hot” one (a simplistic Figure below from Dana-Farber) with the latter reflecting high infiltration of T cells, especially those rich with recognition of specific tumor antigens. Currently the use of TME in the clinic is fragmented; there is no standardized, universal TME score or reporting from path tissue. No less non-invasive.

That deficiency just changed. Another landmark paper in the field was published by Aaron Newman and colleagues in Nature providing a non-invasive assessment of TME via a blood sample (“liquid biopsy” and classifying that with machine learning into “spatial ecotypes” (SE) which predicted response to ICI immunotherapy. Note how both of these landmark papers (thymus and TME) relied on AI to crack the case. Below is a Figure from the TME paper for patients with melanoma and response to ICI therapy according to the 9 different SE profiles. I’ll be talking with Prof Newman soon (June 3rd) for a Ground Truths podcast. Please join us.

The importance of the TME can’t be emphasized enough. A paper this week looked into the issue of pancreatic pre-cancerous lesions. We have over 100 of these PanINs in our pancreas (some people have >1,000) and it wasn’t known why only a very few percent of people have these progress into pancreatic ductal adenocarcinoma (PDAC, Figure). The answer: TME.

I don’t know about you, but the thought of having so many pre-cancerous lesions in our body doesn’t sit well. Especially if our immune system is not protecting us like it should. That’s why the new pre-clinical report of a vaccine that is KRAS-directed, preventing pancreatic cancer, is especially intriguing.

That brings me to the future of preventive or interceptive vaccines. They are now being investigationally applied for people with very high-risk mutations (disease-causing, commonly referred to as pathogenic). But the case for using interceptive vaccines will undoubtedly broaden over time. A recent paper on tumor evolution brought out the concept of directly addressing tumor promoter clones, where the risk in the patient has become much greater, calling for “promotion-preventive” strategies (using the term “promolytics”). Enter interceptive vaccines as a prospect.

Now consider that a person has a poor thymic health score or accelerated aging of their immune system clock. Or by genomic assessment they have cancer predisposition gene variants (not pathogenic mutations) and/or a high polygenic risk score for cancer. Or worrisome CHIP clones that we don’t assess.. This sets up identifying a high-risk group as candidates for interceptive vaccines, whether they are generic to amp up a person’s immune system, or specific to the tumor promoter clones identified by blood testing (liquid biopsy). It’s a window for how we can use all the remarkable process in cancer immunotherapy for wide scale immuno-prevention going forward. I hope I’ve convinced you the cancer immunotherapy field is rich and “hot,” and there’s so much more in store now that we recognize our immune system is central to fighting cancer and we are starting to have ways to assess a person’s immune system before they get cancer. Or to help decide which therapy has the best shot.

NB This post was written by me, no AI. As noted, one image was made with the help of AI. I have no COI related to the content of the post.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in throughGround Truths.

If you are interested, 2 recent interviews posted in the past week

—The age of prevention

—Extending healthspan

Over the years at WSJ, I relied on Joanna’s reviews of technology for many purchases (and things I avoided) reflecting her keen and brutal assessments. I also had fun working with her on some of her video assessments of health technologies.

Her book I AM NOT A ROBOT is both hilarious and highly informative. It is a terrific primer for those who are not fully grounded in AI getting into the history of AI and right up to date with generative AI’s progress.

To get a sense for why AI thought she was the next Tina Fey, check out the back cover! No surprise she got me laughing hard throughout the conversation, no less while reading the book.

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Here is a short YouTube video she posted on her All In AI year of 2025, referred to during the podcast.

Much of her testing of >100 AI products related to medicine and health care, which is what we especially got into during our conversation. She has 3 major rules in her assessment of AI: (1) Ruthless testing; (2) Benchmark vs human; and (3) Costs, which include “compute cost” that we discussed.

Here are some of the things we covered:

1. AI of her blood work

2. AI of mammogram and breast ultrasound, and overall experience as a person with increased risk of breast cancer

3. AI at the dentist (and ”Dentist Deep Clean”)

4. Assessment of Dr. GPT

5. Bill Gates on health AI

6. Her AI Trainer (Chris)

7. Waymo vs Uber

8. Her AI Therapist (Ash)

9. Nothing Bot Sex (her 2 digital lovers)

10. Impact on her children (including 6 Fucking Hamsters, the robodog Sirius)

A big thanks to Ground Truths subscribers from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in through Ground Truths.

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The DL Era of Medical AI

Beginning in 2018, we started to take note that the retina fundus photo, or optical coherence tomography (OCT), had far more information embedded in it when “seen” by AI that was not detected by ophthalmologists. This led to the realization that supervised learning of hundreds of thousands to millions of images yielded superhuman vision. Many papers were subsequently published about AI of the retina image that supported it as a gateway to nearly every organ of the body, no less to the risk of Parkinson’s and Alzheimer’s disease many years before any symptoms appeared. These were each derived from single deep learning models probing the ability for the image to predict a certain condition. I gave a TED talk about this in 2023. A few years ago, Pearse Keane and colleagues published the first retina foundation model, a generalized dataset with many downstream tasks, called (RETFound) from 1.6 million images, demonstrating its prediction of heart disease, stroke, glaucoma, and Parkinson’s disease. This week, a new retinal image foundation model (Reti-Pioneer) from over 100,000 photos was published, adding thyroid disease, gout, and osteoporosis to the long list of conditions, beyond previously established Type 2 diabetes, hypertension, and hyperlipidemia, for determination of level of risk (summarized in the Figure). Who would have thought a retina image was this rich?!

Most people get an eye exam each year or every other year, which typically includes a photo of the retina. More than half Americans had an eye exam last year, or well over 100 million people. Yet none of the extraordinary progress that has been published for superhuman vision of the retina has been incorporated into routine medical practice!

Despite the lack of general use of AI of the retina, at least 4 companies have moved ahead to provide specific results for patients, although sparsely accessible or used in the United States. There’s Optain for cardiovascular risk, Toku Eyes for chronic kidney disease risk and biological age, Mediwhale for cardiovascular and kidney risk, and i-Cognitio Sciences (based in Hong Kong) for Alzheimer’s risk. Although the accuracy of risk of the various conditions is not 100% (= area under the receiver operating characteristic, AUROC of 1.0) this information could be provided for >15 conditions at a nominal cost ($1) or free to all people having an eye exam. But lack of any orchestration of implementing this huge body of work and evidence and issues such as reimbursement have held it back. It’s software that could and should be easily be applied to every retinal image, and someday ought to be part of a “medical selfie” that we could do with automated capture of the fundus using our smartphone and an app readout.

Last week, an AI to detect pancreatic cancer was published which detected ductal adenocarcinoma (PDA) up to 3 years ahead of radiologists (median advance interval 475 days) and the detection of occult PDA almost doubled for AI compared with radiologists (73 vs 39%, respectively, Figure below). The multicenter study also had external validation. Yesterday, the FDA gave approval for access to an experimental drug for pancreatic cancer with very promising results. How about access to an AI to detect pancreatic cancer before it would be picked up clinically?

In China, AI detection of pancreatic cancer via chest and abdominal CT is becoming routine using their validated AI tool known as PANDA. That is to say, the AI is automatically used for detection even though the scan was ordered for something else. That is essence for what has become known as Opportunistic AI. Some examples are shown in the Figure below.

There is a long list of missed imaging opportunities that I’ve summarized in the Table. Just a few weeks ago, as I wrote in a Ground Truths, there’s the ability to obtain a thymus health score via AI of a low resolution chest CT. To get critical information about our immune system health which is not clinically obtainable. We’re leaving so much valuable medical information on the table by not incorporating validated means of AI detection to our medical scans. That doesn’t even take into account what is encoded in electrocardiograms, pathology slides, and many other types of medical images that we’re not extracting with AI.

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The LLM Era of Medical AI

In the April issue, the editors in Nature Medicine published this essay calling for evidence. It reminded me of the famous Cuba Gooding line “Show me the money” from the Jerry Maguire movie.

As opposed to many randomized trials and prospective assessment with external validation of medical image AI, the evidence with generative AI in medicine is lacking. That has not held back the public or physicians from using AI chatbots and LLMs. For the public, according to multiple surveys, 12% of adults are using an AI chatbot every day, or about 40 million people, and estimates range widely from 32% to 73% for having used a chatbot for health information in the past year. According to a recent survey by the American Medical Association in March 2026 of 1,700 doctors, 72% are using genAI for at least 1 use case, and 35% for direct patient care, that is non-administrative, decision making. The graph below extrapolates that for ~1 million physicians.

The next graph indicates the projected use by physicians (from the AMA survey) by the end of 2026. You can see expectations are far different than current use! Note the plan for diagnosis assist.

For AI based decision support, such as making a diagnosis or optimal management of patients by clinicians, what is the evidence? We don’t really have any real-world data. This week in Science Magazine multiple (6) experiments assessing 2 LLMs (Open AI’s o1 and ChatGPT 4) and physicians for case vignettes supported the potential of improved reasoning and, in a simulation of real world emergency room decisions at 3 touchpoints (graph right below) compared with 2 doctors, there was improved initial triage decisions for 01. Most of the many publications use case studies, simulations, and actors as patients. Hardly representative of the messy world of the practice of medicine.

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On the patient side, there’s the same deficiency. A limited exception was a small, prospective, single arm study of 100 adult patients (preprint published comparing a model (AIME) vs primary care physicians for differential diagnosis and management plan, which were shown to be on par. A study of ChatGPT Health for helping to triage patients (simulated) to stay home or go to the emergency room did not fare well for the AI, with many blatant triage errors for real emergencies (such as diabetic ketoacidosis or impending respiratory failure (Figure).

In a randomized trial of LLMs comparing patients assisted by LLMs for 10 medical scenarios (not real-world), the patients did’t do well (Figure) and the conclusion was “We recommend systematic human user testing to evaluate interactive capabilities before public deployments in healthcare.”

There are a couple of exceptions to the lack of real world assessment including a Nature Health paper for use of an LLM in 16 primary care clinics in Kenya and a single center randomized trial in eye care. The latter found a higher diagnostic rate for ophthalmologists using AI (92.2%) compared with those who didn’t (75.4%).

In summary, there is very little evidence for LLMs benefiting patients or doctors for health outcomes. That is not to say that generative AI doesn’t help. It offers strong support for administrative work, such as summarizing charts for doctors, or reviewing labs for patients, or providing relevant publications to clinicians and patients, or helping with pre-authorizations for doctors and billing questions for patients. AI chatbots are helping patients prepare for visits, understand their diagnosis and prescriptions.

But going back to the Nature Medicine’s call out for evidence, we need it. For LLMs to help doctors make critical diagnoses or treatment decisions, that requires prospective studies, ideally randomized, but at the very least rigorous and large, with independent adjudication of health outcomes. And for the public, how do we know entering all one’s data leads to the correct diagnosis or treatment? This week we learned that the symptom quality reported to an AI was deficient as compared to that presented to a physician. How does the benefit of patient access to genAI compare with potential harm?

Summing Up

I’ve reviewed a major paradox whereby AI for medical images, with extensive research dating back more than a decade ago, is not being implemented. Whether it’s a mammogram, a CT scan, a retinal image, or colonoscopy, that have all been extensively studied, their value to improve accuracy and risk assessment in medicine is being missed and essentially disregarded.

On the other hand, tens of millions of Americans are using AI chatbots for medical support, as are a substantial proportion of physicians. There are many reasons to use AI here that are easy to support, because they represent an extension of a web/Google search. Just with much more specificity and depth of response, not something that would be subject to regulatory oversight. But when it comes to making a diagnosis or providing a treatment plan there needs to be proof that LLMs are improving accuracy and outcomes. We’ve already seen multiple studies (again not real world) when the AI performed better for various tasks than the doctor with AI, including the new Science paper this week, indicating we don’t even know yet the optimal way of deploying AI (the human-in-the-loop question). As Raj Manrai wrote in his excellent explainer thread, as one of the senior co-authors of the Science paper: “What do our results actually call for? Prospective clinical trials. Health systems investing in infrastructure now. Monitoring frameworks that track not just diagnostic accuracy but safety, efficiency, and cost. The science has reached a point where trials are justified.” We can’t get to high performance medicine, relying on generative AI for key decisions, without that.

One sticking point. Unfortunately, by the time peer review papers are published, the models assessed are outdated (such as 01, which is text-only, when GPT5.5, which is multimodal, would be current). That can give the AI enthusiasts cover, saying the lack of optimal AI performance was because of a weak and old model. The reality, however, is to prove it. Publish it quickly as a preprint.

We’re just a couple of years into the LLM era for medicine. Waymo started in 2009 and it took more than 15 years of rigorous, iterative work to show its true superhuman performance for outcomes with >90% reduction of serious accidents compared with human drivers. Let’s fix this paradox of medical AI implementation. It’s a two-fold and major undertaking. Amping up the use of medical AI where it’s proven and performing the clinical trials required to justify wide-scale adoption where pivotal evidence is lacking.

NB This post was written by me, no AI. Two images were made with the help of AI, as indicated. I have no COI related to the content of the post.

A big thanks to Ground Truths subscribers (> 205,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. If you’re not a subscriber, please join!

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support a record number of 51 summer interns coming in 2026! These are high school, college and medical students selected from thousands of applicants. We couldn’t do this expanded program without the funds coming in throughGround Truths.

For those of you interested in extending healthspan, my NPR segment this week

“You are a slightly different genetic version of yourself today from yesterday, and will be different yet again tomorrow.”—Roxanne Khamsi

Roxanne Khamsi is one of the leading life science journalists, a contributing writer at The Atlantic, recognized with multiple awards for notable publications. Her new book is entitled BEYOND INHERITANCE. It tells the story about us all being genetic mosaics, chock full of somatic (acquired) mutations, and the implications of those mutations for our health. The myth of a single genome, carbon copy, master blueprint, but instead a dynamic, shifting mosaic in constant internal evolution.

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And here’s the back cover. I was delighted to endorse this book, and reread it to prepare for our podcast. It’s extraordinary and mind-bending.

Here are the topics we covered:

—The Math. 330 billion cells of our ~37 trillion turnover each day, which yields trillions of mutations per day.

—Cellular competition. Winners and losers of an “endoevolution,” Darwinian selection inside us whereby healthy or super-fit mutated cells can crowd out the unfit ones.

This was theorized in 1881 in a book THE STRUGGLE OF PARTS, by Wilhelm Roux

which led to Friedrich Nietzsche’s famous quote “Uniformity is pure delirium.”

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—Single-cell sequencing. How this field catapulted forward owing to the ability to zoom in on genomic mutations at the cellular level.

—Cancer chemotherapy overkill. The routine scorched earth, carpet bombing approach can promote resistance and deleterious mutations, leading to an adaptive strategy of leaving some cancer cells behind, as has been shown to be effective in prostate cancer for improving survival.

—The immune system somatic hypermutation. B cells have the theoretical capacity to produce 1 quintillion unique antibodies (a million trillion). If this weren’t possible, we could die from a common cold. In the Covid pandemic, even before the Omicron variant appeared, Covid booster shots induced hundreds of unique antibodies with neutralization capacity against Omicron. The anticipatory “Red Queen” effect.

—Autocorrection of mutations. They can revert, cure a rare genetic disease from within. It can be considered “Natural Gene Therapy.” Example below of a skin condition Epidermolysis Bullosa with revertant mutations (→ normal skin appearance)

—Different role of acquired mutations through the lifespan. Examples: At embryonic stage, Lines of Blaschko (Image below). In mid-life endometriosis, and in older adults Loss of the Y chromosome (LOY) and Clonal Hematopoiesis of Indeterminate Potential (CHIP). Note these 2 somatic mutation clone conditions are associated with risk of diseases; CHIP-cardiovascular and cancer; LOY-heart failure and Alzheimer’s. I’ve written about CHIP extensively here and here.

—Phenocopy. How a somatic mutation can look the same as a germ-line, inherited mutation, with respect to a disease, and how that is determined.

—Environmental effects inducing somatic mutations: UV light, air pollution, plastics

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—and 3 new papers in the past week!

1. Somatic mutations in the microglia cells of the brain, same as cancer mutations, drive inflammation and are enriched in the Alzheimer’s brain

   

   2.. The potential of “promolytic drugs” to be used to prevent cancer in people who exhibit precancerous somatic mutations

   

   3. How somatic mutations can be the basis of autoimmune diseases

We also spoke about the role of somatic mutations in aging and super aging

A related excerpt at The Atlantic

A Quick Poll

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. We just accepted 51 interns for the 2026 summer, a new record, from thousands of high school, college, and med school student applicants. Our fully loaded cost to do this program is ~$300,000 per year. We’re deeply appreciative for your support of Ground Truths that has enabled this program to prosper and expand.

One more thing:

SUPER AGERS was featured on the CBS Morning Show this week in a segment with Dr. Jonathan LaPook, Chief Medical Correspondent, on the meaning and measurement of biological aging.

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This is one of my favorite books over recent years. Sebastian Mallaby is the Paul A. Cocker Senior Fellow for International Economics at the Council of Foreign Relations and author of 6 bestselling books.

THE INFINITY MACHINE tells the story of AI’s progress over the past 15 years largely, but not exclusively, from Demis Hassabis as the protagonist and leader of DeepMind’, with its 2010 mission statement to achieve superintelligence by 2030. It’s a rich, informative, page turner.

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What We Discussed:

—What is an Infinity Machine?

—Influence of Claude Shannon’s Information Theory and Douglas Hofstadter’s Pulitzer Prize winning book Gödel, Escher, Bach

—Origin of DeepMind in 2010. Prescient. Charter, business plan, included use of agents. How Demis Hassabis was made for the mission!

—Contrasts with Sam Altman and the other AI leaders, the Oligopoly (cover of The Economist this week). For example, Nature papers vs white papers on company websites.

—In March 2016, the same day when DeepMind’s AlphaGo beat Lee Sedol, Hassabis says it’s time to do protein folding (later known as AlphaFold).

—Symbolic AI (historic, deductive, rule-based) vs Deep Learning (Toronto tribe) and Reinforcement Learning (Alberta tribe).

—The Big Miss: DeepMind’s lack of early recognition of the importance of transformer models (leading to ChatGPT), creating a big opening for OpenAI. And why was this missed? The Comeback Story. Is this happening again with coding (not in the book)?

—The AI Arms Race and Hyperscaling

—How the complex relationship between Google and DeepMind evolved

—The Double Cross

—With the dangers anticipated (parallels to Oppenheimer, Manhattan Project, and the atomic bomb), how to promote AI safety?

—Is the major build up of data centers justified?

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

And, if you’re interested on extending healthspan, two recent podcasts/TV segments on SUPER AGERS

On With Kara Swisher

On PBS

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Here’s a quote from Trisha early in the book:

“I’m not a wellness guru. I’m a scientist.”

Another quote from a Vanderbilt professor:

“An effortless, socially appropriately timed bowel movement is the second greatest bodily pleasure known to man.”

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The proportion of people with bowel issues is remarkable, a brief summary:

Some of the topics covered in our lively, fun and highly informative conversation:

—The 3 P’s Propulsion, Pliability, Pelvic Floor

—Ten Myths

—99% of farts have no odor; the 1% that do are from hydrogen sulfide, Pepto-Bismol substantially reduces the latter (and an incredible experiment of people with rectal tubes and judges smelling their gas)

—What is the normal frequency of pooping?

—the Bristol Scale of poop appearance and what it means

—Transit time

—The uselessness and danger of bowel cleanses

—Fibermaxxing

—5 minutes max on the toilet and positions to help propulsion

—Psyllium and laxatives

—The art of wiping and bidets

—Fecal incontinence

—Not to miss urges and the TRPV1 and PIEZO2 receptors

—Impact of coffee, alcohol, NSAIDs (Ibuprofen, aspirin, naproxen, etc), and hydration

—What are the different definitions of constipation?

—What gives poop its color?

********************************************

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If you found this interesting PLEASE share it!

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Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.

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Adrian is a molecular biologist and co-founder and CEO of Genyro, a synthetic biology company. He has published 2 previous books on life science (Life Without Genes and An Intelligent Person’s Guide to Genetics). In this conversation we discussed his new book, cover below and the title of this post.

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ABI. As Adrian puts it, a monumental shift, a second genesis, the “artivolution,” ability to use a molecular Gutenberg press, it’s post-Darwinian.

I made an infographic about the book and our conversation with NotebookLM

The expansion of genome sequences beyond “Fred’s library” (referring to Fred Sanger, father of genome sequencing, little green box)

We talked about the jump from DNA reading to editing and now writing genomes, with the potential of the latter for both good and harm. I disagreed with Adrian about the bright prospects for curing diseases, but there are many possibilities for positive impact, such as intervening vs the climate crisis and sustainability.

We also discussed the large language of life models (LLLMs) and by coincidence my colleagues and I just published a review of these in this Nature Biotechnology (←free access is hyperlinked).

“It should be possible to meet most of humanity’s needs through biologically inspired designs—to solve many global problems, revolutionize health care, extend human lifespan, and create other organisms to order.”—Adrian Woolfson

If you are into life science, I think you’ll find Adrian’s book thoughtful and provocative, even if you don’t agree with some of his optimism like a disease-free organism.

The topic connects with digital biology, a theme that is approached in many editions of Ground Truths, such as this one with Patrick Hsu

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What I consider as 2 landmark papers in Nature this week (here and here) used AI to quantify health of the thymus in 2 large cohorts, and then correlate the metric to a broad array of health outcomes.

In this edition of Ground Truths, I’m going to cover three questions: (1) How was thymus health determined by AI?; (2) How is thymus health linked to key clinical outcomes? and (3) Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years?

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1. How was thymus health determined by AI?

This was accomplished by extensive work developing and validating an AI pipeline for 2 stages, the first for localization and segmentation of the thymus bed, and the second to quantify a digital marker, termed the thymic health score. There’s a lot to this algorithmic development, so I won’t go into all the details, but just provide a rudimentary outline of what was done. The 1st stage used supervised learning with 2 radiologists reviewing 2,461 chest CT scans. That work trained a 3D U-Net model to automatically identify the thymic bed’s 3D cropped region using center of mass coordinates, which reached 99.8% accuracy.

The 2nd stage used a foundation model that was pre-trained with SwAV (which stands for Swapping Assignment between multiple Views), a self-supervised model, that generated a high-dimensional thymus representation of 4,096 features. That compares to the radiology reductionist and subjective scoring of 0 to 3 where 0 means the thymus is fully degenerated and fatty, and 3 is considered dense, intact glandular soft tissue. Notably, the self-supervised learning (SSL) performance was superior to supervised (AUC ~0.75 vs 0.55, respectively) reflecting the shallowness of the 0-3 classifier vs SSL’s holistic, self-taught AI. The thymic health score ranged from 0 to 100, with the highest number indexed to fully preserved thymic health.

The algorithmic work extended to explainability with both Shapely value distribution, meaning the model was holistic not relying on any “magic” pixel, and occlusion sensitivity, demonstrating the model’s performance was not affected by ribs, sternum, lung tissue, but rather focused on the thymic bed directly.

Below are a few saliency maps from the occlusion sensitivity that indicate the thymic bed focus, not affected by neighboring structures, using the jet color scale.

Now the AI was ready for processing ~25,000 CT scans, each over 30 MB files, from the 2 large participant cohorts to provide a thymic health score, it did so in less than 14 hours, which is less than 2 seconds per scan!

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2. How is thymus health linked to key clinical outcomes?

The two cohorts were the National Lung Screening Trial, NLST (N=25,031) and the Framingham Heart Study, FHS (N=2,581) each with baseline demographics and long term follow up of >12 years for health outcomes.

From the NSLT, you can see below that increased age and body-mass index were correlated to reduced thymic health. And, overall, men had reduced thymic health scores compared with women.

There are a lot of graphs in the paper for outcomes, for both the NLST and FHS cohorts. To simplify the major outcomes, below is a composite Figure with striking reduction of all-cause mortality and for the different causes of death. The results were consistent between the 2 cohorts. For example, the cardiovascular mortality hazard ratio average was 0.57 in NLST and 0.38 in FHS (weighted to be 0.53 for the aggregate). The reduction of mortality also extended to digestive diseases and pulmonary disease (data not shown below).

Lung cancer incidence was reduced by 36% for high vs low thymic health (Figure below, with a panel -incidence and b panel-mortality, adjusted for age, sex, BMI, smoking status). Notably, there was a smoker’s paradox: lower incidence and improved survival for lung cancer in smokers who had a high thymus health score.

Smoking was associated with lower thymic scores whereas alcohol was not. Higher thymic health was linked to higher HDL cholesterol, lower triglycerides, lower fasting blood glucose, and lower systolic and diastolic blood pressure. Inflammation biomarkers, such as C-reactive protein and interleukin-6, were elevated in the people with lower thymic health scores.

In their second paper, the same team looked at the relationship between thymic score and outcomes for 3,476 patients receiving cancer immunotherapy. The non-small cell lung cancer progression-free survival was reduced in patients with low thymic health score.

A parallel relationship for survival was seen for other types of cancer including melanoma, breast, and kidney with a 44% lower risk among high thymic scores (Figure). A similar pattern was seen with different immune checkpoint inhibitors.

The thymus health score outperformed programmed death ligand-1 (PD-L1)and tumor mutation burden (TMB) assay of the tumor and was an independent prognostic marker of progression-free survival. In this dataset, a direct connect with thymus score and adaptive immune function was noted with a correlation before cancer treatment for both T-cell diversity and thymus T-cell production (a metric known as T cell receptor excision circles).

Thymus Removal Study

There is a highly relevant citation about thymus function before moving onto ways to rejuvenate it. In 2023, a very important study of thymus removal during cardiothoracic surgery was published, with 1146 patients undergoing thymus removal vs 1146 matched controls (mean age 55 years). The adverse outcomes for thymus removal were striking, with a 2.9 higher risk of all-cause mortality and doubling of cancer incidence, 1.5 fold increase in cancer mortality, and 1.5-fold increase in autoimmune diseases. The immune function showed marked compromise after thymus removal, as reflected by CD4+ and CD8+ T cells (Figure below)

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3. Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years?

In recent months we’ve learned a lot about the process of thymus involution and the pathways by which this may be modulated. Thymus involution is primarily due to loss to thymus epithelial cells (TECs) and there are 2 subtypes with different functions: the cortical, responsible for positive selection of T cells, and the medullary, for negative selection. When adipose tissue infiltrates the thymus, thymic adipocytes are pro-inflammatory, knocking out T-cell output. Likewise, systemic inflammation, or “inflammaging,” from smoking, obesity, and chronic stress promote thymic adipocytes. Now, from preclinical studies, we know about key pathways that account for these processes.

Historically, back in 2014, FOXN1 was recognized as a single master transcription factor essential for TEC function, with studies in mice with forced FOXN1 upregulation leading to thymus regeneration. That laid the foundation for potential regrowth of quiescent thymus cells. It took awhile to find pathways to accomplish this goal and to even refute its role as the master regulator.

The Liver-Thymus Axis

Feng Zhang and his team recently showed that injection of an mRNA vaccine to the liver encoding DLL1, IL-7 and FLT3-L in combination, factors known to support thymopoiesis (Figure), successfully enhanced immune function in aged mice. However, the effect was transient.

The FGF21 Story

Two reports in 2025 addressed the thymus gland’s production of FGF21, a growth factor (fibroblast growth factor 21) and its control of thymus involution. This growth factor is also produced by the liver, but it doesn’t have impact on the thymus in aged rodent models. In contrast, The liver’s hepatocyte growth factor (HGF) has been shown to reverse senescent TEC structural changes. Growth hormone stimulates production of insulin growth factor-1 (IGF-1) in the liver and the thymus. Two small studies in human participants (TRIIM, for Thymus Regeneration, Immunorestoration, and Insulin Mitigation) of 6 and 50 people, respectively, treated with combined human growth hormone, metformin and DHEA, suggested the potential of slowing epigenetic aging and improving thymus mass and function. But the combination of drugs, small sample, and lack of controls make conclusions murky.

Increased thymus FGF21 led to increased CD8 T cells in old mice and extended healthspan and improved physical performance. Building on the previous FOXN1 data, ablation of β-klotho, the obligatory co-receptor for FOXN1, accelerated thymic aging. The benefit to FGF21 was confirmed in a companion paper using an FGF21 knock-in mouse model showing thymus enlargement and increased TECs throughout the lifespan. (schematic Figure below). The accompanying editorial for these 2 papers speculated: “The proposed link between age-associated thymus involution and organismal aging is intriguing, and suggests we might seek to achieve systemic rejuvenation by counteracting thymic involution.”

Other Factors

Lessons from the Axolotl (Mexican Salamander)

In an elegant set of experiments of the axolotl (Figure), known for its complete thymus regeneration after total surgical removal, mediators were identified. Surprisingly FOXN1 was dispensable. But midkine, a growth factor, appeared to be the driver, the initiator of thymus cell growth, survival, and repair. Other components that contributed were Postn+ (periostin-expressing mesenchymal niches) and Ccl19, a chemokine protein from the bloodstream.

RANK and RANKL

RANK (receptor activator of nuclear factor κB its ligand (RANKL) have been considered key regulators of medullary TECs. In a study of both aged mice and human thymus cell cultures, their key role was confirmed, with multiple benefits of resorting TEC function, recruitment of progenitor cells, and T cell development.

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Summing Up

This body of work strongly supports the health of the thymus gland as a critical regulator of human healthspan, not just a correlate or link. The new landmark studies are reinforced by the regenerative biology experimental models that have shown, via an array of mediators, that healthspan of aged mice is at least in part dependent on thymus gland function and its critical role for maintaining adaptive immunity. It sure seems that we’d be better off having an immune reservoir of naive T cells instead of a profile in older adults of exhausted, low quality, memory T cells, with a senescent phenotype.

It is striking that we ignored the importance of the thymus gland for many decades. A wake-up call was the results of the thymectomy matched control study reviewed here, with the opposite of high thymic health score improved health outcomes.

The convergence of AI and healthspan here is notable. The exceptional and laborious work for developing and validating (no less explaining) the AI to quantify thymus health set the foundation for probing the connect the major health outcomes in two cohorts with extensive follow-up. We’ve never had a way to meaningfully quantify the thymus gland before, so this represents important leverage of supervised, self-supervised, and transformer models. The study wouldn’t have been possible without AI. And it begs the question as to whether there are ways we can maintain our thymus at a high health score.

But it’s not so simple to rejuvenate our thymus. There are multiple risks including the induction of autoimmunity, increasing the risk of cancer, and inducing a pro-inflammatory state. For example, factors that increase TEC proliferation could compromise the medulllary negative selection process and leak out auto-reactive (self-attacking) T cells. Thymic cells could be induced to proliferate, but we know, for example, that growth hormone and IGF-1 are associated with an increase risk of cancer. If thymus rejuvenation doesn’t clear out the accumulated senescent cells in older adults, then inflammation within the gland could block the production of TECs. Keeping these risks in mind, we now have identified many ways to keep our thymus healthy as we age that undoubtedly will be tested in clinical trials going forward. Ultimately, the benefit-to-risk tradeoffs will be defined.

In the meantime, we have desperately needed an immunome. As I’ve stressed in multiple prior Ground Truths, we have no test in the clinic to assess a patient’s immune status! It was very encouraging for me to get an email from Hugo Aerts, the senior author of the landmark papers in the days after they were published: “I also wanted to say that your Substack on “Why We Need an Immunome” was inspiring for this work. We found it a very compelling perspective and greatly enjoyed reading it.”

Just having an assessment of a person’s immune status via a chest CT scan, with millions of these performed per year, might help in guiding the right immunotherapy for cancer (e.g. more intensive, combinations for those with low thymic health scores) and help define people who are increased risk for age-related diseases of cancer, cardiovascular, and neurodegenerative. From a practical standpoint, with 20 million chest CT scans performed each year in the United States, opportunistic AI-derived thymic health scores could be routinely provided as part of their interpretation.

The main theme of Super Agers is that we now have many layers of data (genetics, proteins, biomarkers, organ clocks that can be integrated via multimodal AI) for us to define a person’s specific risk decades before one of these age-related diseases leads to symptoms, enabling prevention. From the new studies this week, we can add thymus health score as yet another way to understand a person’s risk, a window into their adaptive immune system and healthspan. And perhaps someday we will be able to safely rejuvenate the thymus, or maintain its health through one’s life, and use the thymus health score to monitor.

NB: I wrote this post (No A.I.)

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Thanks to Ground Truths subscribers (now > 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join!

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Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered.

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Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.