Genes Genomics Genetics Epigenetics and the Environment

Interbreeding between Homo erectus and Denisovans

Proof by analyzing tooth enamel: nine proteins from teeth from six individuals in present-day China

By Dyani Lewis

A realistic model of Peking man spearing a fish.

Ancient proteins were extracted from the tooth enamel of several Homo erectus individuals, including ‘Peking man’ (illustration).

It is well known that human relatives interbred: Homo sapiens with Neanderthals, Neanderthals with Denisovans, Denisovans with Homo sapiens. Now there is evidence for another ancient tryst, between Denisovans and Homo erectus. That’s according to an analysis of ancient proteins extracted from the teeth of six H. erectus individuals that lived in China 400,000 years ago. The work, published in Nature today, is the first genetic evidence of this particular pairing. (1)

Homo erectus played a pivotal part in human history. The species lived over a period from 1.9 million to just 100,000 years ago, a time when Neanderthals, their relatives the Denisovans, and early modern humans all roamed the Earth. Homo erectus was also the first human relative to venture out of Africa and into Eurasia, and as far afield as the Indonesian island of Java in southeast Asia.

Genetic data have been obtained from just a single H. erectus specimen from Georgia, dating to 1.8 million years ago (2). But researchers were unable to identify any unique genetic variants that might distinguish H. erectus from other human relatives.

In China, researchers have found H. erectus remains of varying ages at more than a dozen sites, creating a potential treasure trove for uncovering genetic data for the species. For the new work, Qiaomei Fu, a palaeogeneticist at the Institute of Vertebrate Paleontology and Paleoanthropology in Beijing, and her colleagues focused on teeth from three of those sites. These include the Zhoukoudian site in Beijing, where the famous ‘Peking man’ remains were discovered in the 1920s, along with sites in Hexian in southern China and Sunjiadong in central China. All the teeth analysed date to a similar period in the Middle Pleistocene, around 400,000 years ago.

East Asian marker

Fu and her colleagues extracted protein from the enamel of six H. erectus teeth — five from male and one from female specimens. Scientists have increasingly been looking for ancient proteins in fossil samples because they have been found in specimens that no longer contain DNA. Like DNA, protein sequences can be used to infer relationships between ancient humans.

The team sequenced protein fragments belonging to nine proteins. In one of the proteins — an enamel matrix protein called ameloblastin — the team identified two important amino-acid sequence variants shared by all six H. erectus specimens that set them apart from other human relatives.

“It’s challenging to get those kind of data from ancient enamel, so to have a consistency of results across six teeth was very coincidental,” says John Hawks, an anthropologist at the University of Wisconsin–Madison.

At position 253, the six H. erectus teeth have the amino acid glycine instead of alanine, which occurs in humans and all other human relatives tested so far, including the H. erectus fossil from Georgia. This suggests that the glycine variant could be specific to H. erectus populations in East Asia.

Denisovan trysts

The team also identified a variant at position 273: a valine instead of methionine. Researchers have previously identified this variant in two Denisovans: a 70,000-year-old specimen from the Denisova cave in Siberia, and a specimen from near Taiwan, the age of which is unclear. This indicates that the East Asian H. erectus populations, or a closely related group, passed the variant to Denisovans through interbreeding.

“Given that both groups were close in space and time, it is a reasonable suggestion,” says Tanya Smith, an evolutionary biologist at Griffith University in Southport, Australia.

That scenario is supported by data from older Denisovans that lived closer to the time that the interbreeding probably occurred. The team extracted enamel proteins from a more than 150,000-year-old Denisovan from Harbin in northern China and obtained data for a 200,000-year-old Denisovan from Siberia (3). These Denisovans had both methionine (M) and valine (V) variants, inherited from each of their parents.

‘Ghost’ species

Please read the rest of the article in the attached pdf file.

—DwN

Generative AI is making it astoundingly easy to create scientific fakery that looks real: con?vincing data, tidy plots — and even entire studies that slip past automated checks and human reviewers. In this recent NEJM editorial, the author [Marion V. Nelson, Professor and Chair, Department of Biomedical Informatics, Harvard Medical School] describes a deliberately fabricated dataset and analysis [see attached file], built with help from an AI model that fooled standard anomaly detectors.

The episode highlights a growing problem: technical fixes, such as blockchain, may offer reassurance, but they cannot solve the deeper cultural pressures in science — (that reward speed, and novelty — over care and verifi?cation). What might help is the harder work of valuing replication, transparency, and rigor, because AI can amplify whatever incentives we humans set. ☹

DwN

FDA Approves First Gene Therapy for Severe LAD-1

M. Alexander Otto, PA, MMSc

March 27, 2026

The FDA has granted accelerated approval for the gene therapy marnetegragene autotemcel (Kresladi, Rocket Pharmaceuticals) for the treatment of pediatric patients with severe leukocyte adhesion deficiency type 1 (LAD-1).

The approval is specifically for children with LAD-1 — caused by biallelic variants in the ITGB2 gene who lack a matched sibling donor for hematopoietic stem cell transplant (HSCT). It marks the first gene therapy for the ultrarare disease.

LAD-1 is an inherited immune disorder that occurs in about 1 in 1 million people worldwide. Mutations in the ITGB2 gene leave white blood cells without functional CD18, a protein necessary for the cells to adhere to blood vessel walls and migrate into infected tissue.

Children born with severe LAD-1 develop recurrent, life-threatening bacterial and fungal infections that respond poorly to antimicrobials and require frequent hospitalizations. Without a curative allogeneic HSCT, up to 75% of children with severe disease die before age 2.

Marnetegragene autotemcel (marne-cel) is an alternative to allogeneic HSCT and the first gene therapy approved for LAD-1.

It’s a one-time treatment consisting of patient-derived hematopoietic stem cells that have been genetically modified to introduce functional copies of the ITGB2 gene. After 4 days of myeloablative busulfan conditioning, patients receive a marne-cel infusion 1-2 days later; the cells migrate to the bone marrow, proliferate, differentiate, and produce white blood cells expressing CD18.

Accelerated approval was based on a phase 1/2 study in nine children demonstrating that marne-cel increased neutrophil CD18 and CD11a cell-surface expression through month 24 post-infusion. Sustained increases in the two biomarkers serve as a surrogate endpoint that is “reasonably likely” to predict clinical benefit, the FDA said.

Confirmation of clinical benefit will be based on longer-term follow-up data from the ongoing clinical study, as well as through a postmarketing registry, Rocket Pharmaceuticals said in a press release.

In the study, the most common treatment side effects included anemia, low platelet and white blood cell counts, mouth sores, upper respiratory and other viral infections, fever, febrile neutropenia, nausea, vomiting, skin infection, rash, vascular device-related infection, and increased liver enzymes.

Because the therapy uses a lentiviral vector (LVV), LVV-mediated insertional oncogenesis may occur. Hematologic malignancy is a lifelong risk following treatment, the company said.

M. Alexander Otto is a Physician Assistant with a M.S. degree in Medical Science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape.

This is an interesting and unexpected story. GEITP came across this Nov 2025 article (“Integrative phylogenomics: positions SPONGE at the root of the animal tree”), which would counterbalance the 25 Apr 2026 email blog — claiming that the comb jelly, not the sponge, was the root of the animal tree-of-life. However, when we attempted to download the 6-page Research Article (Science 13 Nov 2025; 390: 751-756) and the 2-page editorial (Science 13 Nov 2025; 390: pp 673-674 editorial), the journal Science reported that this study has been retracted.

5 FEBRUARY 2026 Science

RETRACTION of Research Article “Integrative phylogenomics positions sponges at the root of the animal tree”:

On 13 Nov 2025, Science published the Research Article “Integrative phylogenomics positions sponges at the root of the animal tree” by Jacob L. Steenwyk and Nicole King (1). The authors alerted us that errors in the analysis pipeline had affected the results — to an extent that the data are no longer reliable.

Two aspects of the data analysis introduce artifacts. First, an imbalance between the number of sponges and ctenophores in the dataset biased one of the scoring metrics, thereby influencing the outcomes. Second, part of the analysis involved collapsing internal nodes, which was not properly accommodated by the software used. The authors thank Casey W. Dunn and colleagues (Department of Ecology and Evolutionary Biology at Yale University), for bringing this to their attention, as detailed in an eLetter and in Steenwyk and King’s eLetter Response — both of which are available at https://www.science.org/doi/10.1126/science.adw9456#elettersSection. Given these issues, both authors have requested a Retraction. Science is therefore retracting the Research Article.

–H. Holden Thorp, Editor-in-Chief, Science

REFERENCES AND NOTES

1. J. L. Steenwyk, N. King, Science 390, 751 (2025).

The first pdf attachment is the 2-page 13 Nov 2025 editorial, which is a valid summary (except it is based on the retracted article). The second pdf attachment includes the 5 Feb 2026 Retraction Note. ☹ At this point in time, GEITP continues to favor the “comb-jelly first” hypothesis… 😊

DwN

During evolution, survival of every species has always depended on the ability of the organism to be able to: [a] find food, [b] avoid predators, and [c] reproduce. Photoperiodic time measurement is the ability of plants and animals to measure differences in day versus night length (photoperiod) and use that information to anticipate critical seasonal transformations — such as annual temperature cycles. This timekeeping phenomenon triggers adaptive responses in higher organisms, such as gonadal stimulation, flowering, and hibernation.

Many branches of the eukaryotic tree-of-life have evolved the ability not only to react to, but also to anticipate the changing seasons and proactively adjust their behavior and physiology by measuring seasonally changing photoperiods (PPs) with a timekeeping mechanism that often requires a circadian clock. However, prokaryotes with very short generation times have rarely been considered to harbor such a prolonged temporal program.

Cyanobacteria (which are prokaryotes — microscopic, single-celled organisms with a single unpaired chromosome, which do not have a distinct nucleus or other membrane-bound internal parts) — with doubling times as short as 5 to 6 hours — have nevertheless become productive model organisms for the study of circadian (daily) rhythms, with a core clock mechanism comprising only three proteins that can be reconstituted in vitro. Cyanobacteria are found in a wide range of latitudes and, as such, are exposed to distinct annual changes in light and temperature in their natural environment. Authors [see attached] therefore tested whether cyanobacteria are capable of timekeeping on a temporal scale that is even longer than daily, i.e., photoperiodic time measurement (PPTM) in promoting adaptive cold-resistance responses to seasonal changes. [But — how in the world would anyone study circadian and clock-like and seasonal rhythms — in bacteria??]

Cells of the unicellular cyanobacteria were grown at 30°C and exposed to eight continuous 24-hour cycles of: short days (LD8:16, 8 h of light followed by 16 h of darkness), equinox (LD12:12), or long days (LD16:8). After this exposure, the bacteria were resuspended and exposed to ice-cold temperatures for various durations, after which their survival was assessed (Fig. 1A and fig. S2). Prior exposure to short days led to ~2-3 times higher survival of wild-type (WT) cyanobacteria, compared with those that were exposed to equinox or long days (Fig. 1B). This differential survival was not observed in arhythmic cells in which the circadian clock genes kaiA, kaiB, and kaiC had been deleted (DkaiABC; Fig. 1B) or in mutants that lacked other components of the core clockwork or its output pathways (DkaiA, DrpaA, DcikA, DsasA; see fig. S3, A and C).

To assess whether cold resistance was influenced by the time of day of the assay, authors repeated the experiment in the morning, midday, and evening of the LD cycles (Fig. 1C for WT and fig. S4A for DkaiABC). The survival differential was highest when the assay was performed in the early day, but for all sampled times, WT bacteria survived cold best after exposure to short PPs — as compared with long or equinox PPs; arhythmic DkaiABC cells showed no effect of PP or time of day on survival (Fig. 1Cand fig. S4B).

An intriguing aspect of photoperiodic responses in general is that they are often “history-dependent” — i.e., an organism’s interpretation of a PP is dependent on the prior exposure conditions. Consequently, a common characteristic of bona fide PPTM is that multiple 24-h cycles of inductive PPs are often required to elicit a complete response. This has been termed a “photoperiodic counter”.

Given their short generation time, authors wondered if prokaryotic cyanobacteria could remember and integrate a PP signal that extended over multiple cycles and generations. A single cycle of different PPs did not produce differential survival (Fig. 2A); at least four cycles seemed to be necessary to achieve the full magnitude of the photoperiodic response (Fig. 2B).

The development of differential survival among PPs appeared to be mainly caused by a progressive gain of resistance in short days, rather than by a further loss of cold resistance in long days. Therefore, the photoperiodic response required cumulative exposure to multiple cycles and a PP-counting-memory. The short-day gain of cold resistance that was achieved by four PP cycles spanned at least ~3.2 generations for WT cells (see Fig. 2C). Again, cells without a functional circadian clock expressed a PP-independent increase in cold resistance as the number of LD cycles increased (figs. S6, A and B). Authors tested how long the cold resistance lasted after the photoperiodic cues were removed. After their standard pretreatment of eight PP cycles, they transferred the cells to either constant light (LL) or constant darkness (DD) and measured thereafter at 24-hour intervals. Transfer to LL led to a general decrease in survival of the short PP–exposed cells (Fig. 2D and fig. S6F), whereas the opposite was true for release to DD (figs. S6, D and E). In both cases, after 24 hours in constant conditions, short PP–exposed cells tended to survive slightly longer than cells from the other PPs [but these differences were not statistically significant (fig. S6, F and G)]…

To be certain that their results were dependent on the duration of the PP and not simply a differential exposure to light — (which is relevant for a photosynthetic organism) — authors tested whether changes in light intensity could influence this photoperiodic response. Cells were exposed to fluence rates of 20 mEm−2 s−1, 40 mE m−2 s−1 (their standard light intensity), and 80 mE m−2 s−1 (Fig. 2E). Recovery of the DkaiABC cells from cold was a simple function of fluence rate: Higher light intensities led to lower survival than low light intensities (see Fig. 2F and fig. S7 for the full survival curves at each light intensity).

In contrast, whereas overall survival was also correlated with fluence rate for WT cells, in this case WT cells exposed to short days survived better than those exposed to long days at all intensities (Fig. 2F and fig. S7B), indicating that WT cells appear to integrate temporal information with light intensity.

Taken together, these data indicate that the PP-dependent response to cold exposure develops over multiple LD cycles that span multiple generations of cyanobacteria. These data also suggest that cells in their natural environment integrate multiple factors (e.g., light intensity) along with PP to program the optimal adaptive response.

Unexpectedly, the authors of the attached study observed this capability in cyanobacteria — unicellular prokaryotes with generation times as short as 5-6 hours. Cyanobacteria exposed to short, winter-like days developed enhanced resistance to cold mediated by desaturation of membrane lipids and differential programs of gene transcription, including stress response pathways. As far as eukaryotes, this photoperiodic timekeeping required an intact circadian clockwork and developed over multiple cycles of photoperiod. Therefore (believe it or not), photoperiodic timekeeping evolved in much simpler organisms than previously appreciated and enabled genetic responses to stresses that recur seasonally.

Long-lived plants and animals clearly regulate their physiology according to seasonal changes in day length to appropriately adjust their physiology. These authors found that cyanobacteria can do the same — even though individuals only live for a few hours, a time shorter than a single daily photoperiod in most eukaryotes. Exposure to short photoperiods (characteristic of winter) stimulated these cyanobacteria to adjust their membrane lipids and gene expression to accommodate cold conditions. These responses required a functional circadian clock. Thus, population-based sensing of photoperiod appears to have evolved very early, perhaps as a refinement of stress pathways.

These data represent a great example of gene-environment interactions and support the idea that photosensitivity sensor pathway(s) likely existed as early as the Last Universal Common Ancestor (LUCA) — estimated now by some [Moody et al., Nat Ecol Evol. 2024; 8: 1654-1666] to have occurred as early as 4.2 Ga (Giga-annus; or 109 years ago). 😊

DwN

Science 6 Sept 2025; 390: 1105-1111

See attached URL for the latest review on Ctenophores, the likely phylum that evolved earlier during evolution than sponges (Porifera).

DwN 😊

Ctenophores Aren’t Just Beautiful. They’re Biological Wonders.

GEITP reports scientific articles (almost always) having a “gene-environment interactions” theme — but also including examples of fraud and corruption. This story is unusual/remarkable/incredible because it’s not the scientists being corrupt, but rather a publisher and specific editor — overriding the opinions of most of the editors of the journal. And the story spans at least 25 years. ☹

To begin our story, Williams GM et al., published a thorough review in Regulatory Toxicology and Pharmacology (RTP) in 2000, “Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans,” [Regul Toxicol Pharmacol (RPT) 31: 117–165. [PMID: 10854122]. Gary M Williams et al, were collaborating with Monsanto toxicologists — who had the details of the industry-sponsored studies, which were proprietary. This comprehensive review paper concluded that glyphosate, the active ingredient in Monsanto’s Roundup™ herbicide, posed no significant health risks to humans based on exposure data available at the time. TWENTY-FIVE (25) YEARS LATER(!!!!), there was a decision by the co-Editor-in-Chief of Regulatory Toxicology and Pharmacology, Prof. Martin van den Berg, to retract this extremely popular highly cited 2000 review article by Williams, Kroes, and Munro…(!!)

It came as no surprise that this decision has elicited widespread concern and criticism within the scientific community. Issued in late 2025, the retraction decision cites “procedural concerns” including: “potential ghostwriting, undisclosed conflicts of interest, and omission of certain unpublished studies, invoking Committee on Publication Ethics (COPE) guidelines” — despite lacking any evidence of fraud or scientific flaws. A rebuttal article (written by 66 angry coauthors) was therefore developed and submitted to RTP.

This editorial [see attached] argues that the retraction decision “involves editorial overreach and misapplication of the guidelines.” The alleged omissions stemmed from “proprietary data access limitations,” but were disclosed in the original paper. Subsequent reviews by several independent expert panels and regulatory authorities with access to all glyphosate data — including the studies cited by the retracting editor — reached similar conclusions. Claims of ghostwriting were previously investigated and found lacking, including a declaration by European Food Safety Authority (EFSA) as to the clarity of the conflict disclosures. Attempts to receive a rebuttal from the three coauthors of the 2000 review failed — primarily because two of the three coauthors are no longer alive, and Gary Williams (now 90 years old) is no longer in good health.

The retraction’s timing, reliance on litigation documents, and apparent biases that were not disclosed in the retraction notice — raise “questions of ideological interference.” 😉 Absent substantive rebuttals based on scientific merit, rather than speculative claims of inappropriate authorship and data access, this retraction decision sets a dangerous precedent for retroactive censorship — potentially chilling beneficial industry-academic

collaborations and eroding trust in the integrity of scientific publishing. With the strongest conviction, these 66 angry coauthors [see attachment] assert that “retracting a paper without scientific flaws is not protection — it is censorship, pure and simple.” Therefore, they are “calling for the immediate reversal of this flawed and unjustified retraction — in order to preserve trust in peer-reviewed scientific literature.”

This work [see attached preprint] was first submitted on 27 Feb 2026, as a proposed Commentary to Regulatory

Toxicology and Pharmacology — as a courtesy to the retracting editor Dr. Martin van den Berg, of RTP and to the journal, Elsevier. Subsequently, it was withdrawn because co-Editor-in-Chief Dr. van den Berg would only accept a truncated version that neither transparently listed all 66 authors nor permitted a full exposition of his retraction decision.

This work [see attached preprint] was then invited as a Guest Editorial in Archives of Toxicology (AoT), receiving

full acceptance in March 2026. Following acceptance, publication in AoT was repeatedly and unjustifiably delayed due to inappropriate interference by the publisher of that journal (Springer Nature) — over the objections of the Editor-in-Chief and the Deputy Editor-in-Chief.

As authors, editors, peer-reviewers, and members of the editorial boards of prominent journals in various scientific fields, including the field of toxicology and the journal RTP, the 66 angry coauthors [see attached] believe that the retraction of the Williams et al. (2000) review is both unjustified and indefensible. The decision was not grounded in any scientific error or fraud in the retracted article — but appears to reflect a subjective ideological perspective that fails to consider and account for all the facts. This solo editorial decision sets a dangerous precedent in which historical, well-received papers are withdrawn on alleged procedural technicalities — long (25 years) after the standards by which they were originally accepted may have changed…!!

Indeed, the Committee on Publication Ethics (COPE) guidelines were first published in 1999 and have undergone significant revisions in 2004, 2007, 2011, and 2017, (COPE, accessed 2//20/2026). Moreover, long-delayed retractions such as this (25 years after the original publication) are likely to find the authors retired or no longer alive and thus in no position to defend themselves or the data they had published. Instead, the proper answer to any editorial qualms about this paper would have been to seek substantive, refereed scientific rebuttals rather than to issue a retraction with no objective evidence to justify such an action (Siddique et al., 2024). This retraction underscores even more importantly, broader concerns about ideological interference in scientific publishing. Whereas COPE guidelines claim an intent to protect journal integrity, their application in the retraction of Williams et al. (2000) appears to be internally inconsistent and arbitrarily selective, retroactively discrediting valid research prejudicially without offering new evidence of scientific misconduct or weakness. This decision risks a chilling effect on the traditionally vibrant industry-academic partnerships that provide many advantages and benefits from robust data access in toxicology (Walker and Roberts, 2018). The scientific community at large must demand greater accountability from editors to prevent such inappropriate retroactive decisions from eroding trust in peer-reviewed literature (Siddique et al., 2024).

This episode also highlights how egregiously the COPE [Committee on Publication Ethics] guidelines can be misapplied and calls into question whether publishing guidelines are effective in protecting scientific integrity, or merely shield editors and publishers from accountability and responsibility. Amidst a waning need for corporate publishers’ involvement in scientific communication and growing concerns about their ethical effectiveness, scientists should consider alternative models for refereed publication (e.g., EXCLI Journal [EXCLI, 2026]). ☹😊

Attached are corrected page proofs, EXCL-1, in press. For those unfamiliar with the EXCLI-Journal, I strongly encourage you to visit their website to learn of its history and independence of any commercial publisher. Also — note that the EXCLI-J journal has an impact factor of 6.2. In my humble opinion, more journals like EXCLI-J must be established to counter the assault on science that has been so thoroughly exposed by the tortuous process that we have endured trying to publish our editorial.

—-Christopher J. Borgert, Ph.D.
President & Principal Scientist
Applied Pharmacology and Toxicology, Inc.

COMMENTS”
… And the Plot continues to thicken… ☹☹

DwN

From: Miller, Walter
Sent: Monday, October 5, 2026 10:33 PM

Dan, I was able to find the Williams et al. 2000 review [see pdf file, now attached] — and I downloaded it yesterday with the ‘Scarlet Letter’ attached to every page. Even ‘Hester’ only had to wear one letter ‘A’…!! “Editorial overreach” is an understatement; this was an extra-judicial killing. But I have just re-confirmed that it is still there via Google Scholar, so habeas corpus is not dead yet; they are not trying to hide the body.
Walt

Walter L Miller, MD
Distinguished Professor, Emeritus
University of California, San Francisco

From: Guengerich, Frederick P
Sent: Monday, October 5, 2026 5:53 PM

In my experience as Assoc Editor for J Biol Chem for many years, Dan — this is totally unethical.

But the publishing houses are getting sleazier & sleazier—gouging $ from everyone they can—authors, libraries…..

At JBC, we stamped them and left them on PubMed with a note — and explained why they had been retracted.

(Of course, now Elsevier is handling JBC, too, so … who knows.)

Fred

—————
F. Peter Guengerich, Ph. D.
Vanderbilt University School of Medicine

From: Daniel W Nebert
Sent: Monday, October 5, 2026 5:19 PM

On 3 Oct 2026 I checked on PubMed — and the 2000 Williams et al. review was there (although it said “Retracted.”)…

Then, 4 Oct around noon, I decided to download it and add to my GEITP blog as an attachment. And it had completely DISAPPEARED…!!

—DwN

From: Guengerich, Frederick P
Sent: Sunday, October 4, 2026 6:15 PM

This is really serious, Dan. ——I totally agree, Fred. This is such a flagrant violation of ethical behavior.

I would have signed off on this, if asked. ——Me too.

I wonder if the plaintiff’s lawyers are in the mix here?????

Fred

—————
F. Peter Guengerich, Ph.D.
Tadashi Inagami Professor of Biochemistry
Department of Biochemistry
Vanderbilt University School of Medicine
Nashville, TN 37232

From: Miller, Walter
Sent: Sunday, October 4, 2026 6:25 PM

This is a wonderful example of European efficiency. Our Supreme Court usually makes scientifically absurd pronouncements, but in this case, it seems that one, and only one, person (who lacked the testicular fortitude to author his pronouncement) was needed to ascribe the ‘Scarlet Letter’ to this review. ——Walt, My feelings exactly. My colleague who alerted me to this scandal had been on the RTP Editorial Board for ~10 years — but resigned because of this flagrant senior editorial decision.

I have no opinion about glyphosate, but I am tired of reading newspaper articles about single individuals getting huge settlements for every conceivable disorder. Are we to expect that our work from decades past will be subject to contemporary revisionism? ——I also had that same thought: “In 2050 or 2060, will some “individual rogue editor” decide that one of my sentinel publications should be retracted?” ☹ —DwN

Walt

Walter L Miller, MD
Distinguished Professor, Emeritus
University of California, San Francisco
Emeritus Chief of Endocrinology
UCSF Benioff Children’s Hospitals

From: Anonymous
Sent: Sunday, October 4, 2026 5:13 PM

Dan: This is a victory for the trial lawyer’s mafia. It does not put establishment science in a good light. I hope it will soon be reversed.

From Anonymous Physics Professor Emeritus

This GEITP email blog is different from all previous ones over these past 18 years — because the attached 2026 publication (see pdf file attached) originates largely from two past GEITP blogs (one in 2024, the other in 2021). To give the Reader some background, planet Earth is estimated to have formed ~4.54 billion years ago (BYA; or the abbreviation “Ga”, for giga-annum). The Last Universal Common Ancestor (LUCA) is believed to have been a prokaryote-like organism that is the assumed ancestor of all living things on Earth.

The prevailing School of Thought believes LUCA has been thought to have lived between 3.8 and 3.5 Ga, meaning that it would have emerged around the time the three domains of life (Archaea, Eubacteria, and Eukarya) came into being. [Archaea (Archaebacteria) are single-celled microorganisms (most likely the oldest and therefore closest to LUCA) that can live in extreme environments (i.e., hot temperatures, high pH levels, low temperatures, or salty environments). Archaea have some features of both Eubacteria and Eukarya (i.e., no nucleus to house their single chromosomes of DNA, and a similar structure to Eubacteria). Eubacteria are single-celled microorganisms that also have no nucleus to contain their single chromosome of DNA. Eukarya are the more complex organisms — whose cells almost always have a nucleus, paired chromosomes inside that nucleus, and other membrane-bound organelles — which then gave rise to protists, plants, fungi and animals.] “Between 3.8 and 3.5 Ga” [4.54 minus 3.65 + 0.15 = 0.89 Ga, i.e., 0.89 billion] would mean LUCA arose ~890 million years after Earth’s formation.

Theories as to how life might have evolved — include the RNA First theory (suggesting ribonucleic acid served as the primary genetic and catalytic precursor for early evolution); Metabolism First models (alkaline hydrothermal vents provided a continuous source of energy and mineral catalysts for prebiotic chemistry; porous rock formations on the ocean floor naturally generate proton gradients that can drive primitive energy transfers and organic synthesis); Concatemer First (organic building blocks formed naturally from primordial environmental conditions; amino acids, nucleotides, and lipids spontaneously assemble when basic chemical solutions are exposed to energy sources like heat or electrical charges); and DNA First (nucleotides forming random concatemers, leading to formation of early genes, etc.).

Then, on 12 Jul 2024, Moody et al. published a paper, which GEITP shared 17 Jul 2024: authors used improved methods of analysis, suggesting that LUCA likely appeared around ~4.2 Ga years ago — i.e., only 340 million years, instead of 890 million years after Earth’s formation. When I shared this article with GEITP, we realized that “340 million years ago” would still be during the Hadean Eon, meaning early Earth exhibited a molten surface, intense volcanic activity, and constant bombardment by asteroids and comets, so I raised the question: how could early life be protected from the violent environment of the Hadean Eon — if origin-of-Life arose from the RNA First, Metabolism First, Concatemer First, or DNA First theories?

Then (from GeneWhisperer.com) I remembered a GEITP email blog from 29 Oct 2021, describing Prof. Doron Lancet’s group — proposing what might have occurred before the existence of RNA. First, there emerged micellar protocell precursors, much simpler than the more commonly studied vesicle-based protocells. This viewpoint is based on a growing body of evidence that lipid micelles (although not living things) are capable of harboring catalysis (i.e., acceleration of a chemical reaction by a catalyst), forming catalytic networks that undergo self-reproduction and pass compositional information from one “generation” to the next. They call it the “Lipid First model.”

Authors therefore proposed that micelles — comprising molecularly diverse amphiphiles [i.e., chemical compounds that possess both hydrophilic (polar, water-loving) and lipophilic (nonpolar, lipid-loving) properties] could be evolutionary precursors to more elaborate protocellular entities, en route to life as we know it. They suggested, collectively, that autocatalytic sets could become “mutually catalytic lipid networks,” and it had been shown — via details of the graded autocatalysis replication domain (GARD) chemical kinetics model — how mixed lipid assemblies could undergo compositional self-reproduction. Their studies focused on the possibility that life began with nanoscopic (i.e., extremely small, on a scale of one-billionth of a meter) lipid micelles, and reveals how experimental evidence regarding micellar catalysis substantiates the authors’ predictions.

Finally, this latest review paper (in 2021) emphasizes that micellar origin of life is plausible with prebiotic “messy chemistry.” Thus, their paper lends credence to what is becoming a viable scenario for a “pre-RNA origin of life.” Several GEITP-ers proposed that we combine these two landmark publications and submit it as a paper for publication. Which we did (see attached publication, in June 2026). 😊

DwN

Hum Genomics June 2026; 20: 133

Genetic Testing Before Prescribing: Routine or Selective?

Susana Almenara; Francisco Abad-Santos

September 10, 2026

Providing the right treatment to the right individual at the right time has been the primary goal of medicine for decades.

Although personalized medicine seems difficult to achieve, its development has been driven by the identification of biomarkers that can guide targeted therapies, particularly in oncology. This approach has substantially changed the course of diseases, including chronic myeloid leukemia, certain subtypes of breast cancer and non-small cell lung cancer, and metastatic melanoma. It is now expanding into other clinical areas, with the potential to improve prevention, diagnosis, treatment, and prognosis across a growing range of conditions.

On June 23, 2023, an agreement establishing the Catalog of Genetic Tests for the Common Portfolio of Services of the Spanish National Health System (NHS) was approved.

On June 18, 2024, a ministerial order updating the Common Portfolio of Services in the field of genetics and establishing an Advisory Committee for the portfolio was published in Spain’s Official State Gazette.

The regulation was developed with direct contributions from experts representing Spain’s Autonomous Communities, various scientific societies, the Carlos III Health Institute and the Spanish Network for the Evaluation of Health Technologies and Services.

Article Key Points

Spain NHS CGEN: 12 pharmacogenetic markers for 22 drugs.
Routine pre-treatment testing required for some labels: HLA-B*57:01, DPYD, TPMT/NUDT15.
Preemptive genotyping + EHR storage supports future prescribing; useful in polypharmacy, age >70.
PREPARE trial: 12-gene panel ↓ actionable ADRs ~30%.
Current use remains reactive; major gaps in statins, PPIs, opioids, NSAIDs, psychotropics.

Dive Deeper

Which pharmacogenetic panels improve primary care safety?

What EHR systems best store genotype results?

Which statin genes predict myopathy risk best?

See clinical implications for practice. Summarize this article in patient-friendly language. See clinical sources and evidence-based research

This marked the beginning of a process to define and expand the genetic tests included in the NHS common portfolio, with the goal of improving prevention, diagnosis, treatment, and prognosis for various high-impact diseases while promoting equitable access across the country.

Spain’s National Health System operates the Common Catalog of Genetic and Genomic Tests (CGEN) to guarantee nationwide, equitable access to molecular diagnostics and pharmacogenomic evaluations. The CGEN currently includes 12 pharmacogenetic markers for 22 drugs.

Pharmacogenetics examines how genetic markers influence an individual’s response to a specific medication or the risk for adverse effects, both within and across populations. The goal is to move toward more individualized treatment by selecting the most effective medication for each individual from the outset while minimizing the risk for adverse effects. Including these tests in the common portfolio provides a framework for requesting them within the NHS, although implementation may vary across autonomous communities and healthcare centers.

Some of these genetic markers are included in drug labeling, making testing necessary before treatment initiation. Examples include HLA B57:01 before treatment with abacavir, DPYD testing before treatment with fluoropyrimidines, and TPMT and NUDT15 gene testing before treatment with thiopurines, such as azathioprine. Other markers are relevant only to certain populations because they are uncommon outside these groups. One example is testing for the HLA B15:02 genetic marker, which is required before carbamazepine treatment in individuals of Asian ancestry.

The range of tests included in the portfolio also makes an ongoing review and updating necessary. For example, since the 2023 agreement, mavacamten has been introduced in Spain for the treatment of obstructive hypertrophic cardiomyopathy. Its prescription information requires knowledge of the CYP2C19 phenotype to select the initial treatment dose.

Other drugs, including lecanemab and donanemab, have been approved for the treatment of Alzheimer’s disease but are not yet marketed in Spain. Testing for the number of APOE epsilon 4 copies before starting lecanemab is critical because the drug is contraindicated in individuals who are epsilon-4/epsilon-4 homozygotes.

Another potential pharmacogenetic application, not yet included in CGEN, involves mitochondrial ND4 gene polymorphism (mtND4 m.11232T > C). To date, this variant has been described only in individuals of Venezuelan maternal ancestry and has been proposed as a marker associated with increased sensitivity to halogenated anesthetics and a higher risk for severe neurologic toxicity.

Therefore, the current catalog is a starting point that includes the first prioritized areas and will be expanded progressively. It will be updated periodically following proposals from the Advisory Committee for the Common Portfolio of Services in Genetics

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Technical update proposals will be submitted to the Commission on Benefits, Insurance, and Financing, after which the tests will be formally approved through an agreement by the Interterritorial Council of the NHS.

This entire process of updating and finalizing the portfolio is carried out through the advisory committee, which includes representatives from autonomous communities, and its technical working groups, which involve relevant scientific societies to ensure that updates are based on the best available scientific evidence. The Ministry of Health also has information systems for monitoring portfolios, allowing the included tests to be consulted online.

Pharmacogenetics in Primary Care

The integration of pharmacogenetics into primary care is supported by growing evidence of its cost-effectiveness for both individual tests and multigene panels. This economic feasibility is supported by the declining cost of genomic technologies and their increasing availability in clinical practice.

For this transition to be effective and safe, clinical decision support systems have been proposed to help physicians interpret genetic data and minimize prescription errors. Within this framework, preemptive genotyping has emerged as an efficient approach because genetic results can be stored permanently in the electronic health record and accessed for future prescription without repeating the tests.

This approach may be particularly useful for managing individuals with multimorbidity and polypharmacy, especially adults older than 70 years, among whom the probability of receiving ≥ one medication covered by the active pharmacogenomic guidelines is close to 90%.

Preemptive genotyping has been shown to have clinical utility in several studies. The PREPARE study is probably the most important pharmacogenetic implementation trial conducted to date. The European, multicenter, open-label, cluster randomized trial included nearly 7000 individuals from seven countries. A preemptive 12-gene pharmacogenetic panel combined with the Dutch Pharmacogenetics Working Group provides evidence-based dosing and drug-selection recommendations to tailor medication use according to a patient’s genetic profile.

Pharmacogenetically guided prescribing reduces clinically relevant adverse drug reactions by approximately 30% in patients with actionable gene-drug interactions, a major finding of the study. The study showed that a multigene panel could be implemented in clinical practice to improve medication safety, although it included individuals from primary care, as well as hospital and specialist settings.

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Several treatments involving pharmacogenetic testing are supported by sufficient evidence and international clinical guidelines, with some particularly relevant to primary care. However, the use of pharmacogenetics within the NHS remains limited and, in many cases, is reactive, with testing performed after problems with efficacy or safety have emerged, instead of being incorporated into a preventive strategy. This applies particularly to medications including statins, proton pump inhibitors (PPI), opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and psychotropic drugs.

For statins, CGEN limits the use of the SLCO1B1 genetic marker to individuals who have previously experienced severe muscle toxicity with simvastatin.

However, international guidelines recommend preventive testing and extend consideration to other statins and genetic markers, including CYP2C19 genotyping for fluvastatin and ABCG2 genotyping for rosuvastatin.

Another drug widely used in primary care and included in CGEN is omeprazole. The drug is primarily metabolized by CYP2C19, and genotyping can help predict the treatment response at standard doses. In the Spanish guidelines, the use of this marker is restricted to individuals with Helicobacter pylori infection who do not respond to omeprazole. By contrast, international guidelines propose CYP2C19 testing before treatment to help select the dose of omeprazole and other PPI for indications including H pylori infection, gastroesophageal reflux disease, gastric and duodenal ulcers, pathologic hypersecretory conditions, and eosinophilic esophagitis.

The only psychotropic drug included in the Spanish drug formulary is pimozide, which is associated with the CYP2D6 genetic marker for drug metabolism. Testing for this marker can be requested before treatment to reduce the risk for QT interval prolongation, a serious adverse effect related to the drug’s concentration in the blood.

The catalog does not currently include initial pharmacogenetic testing for numerous opioids, NSAIDs, antidepressants, antipsychotics other than pimozide, or cardiovascular drugs. However, when a genotype has already been obtained for another indication, the results may be used to guide the selection or dosage of medications metabolized by the same genes. These include various antidepressants and antipsychotics, tramadol, codeine, hydrocodone, flecainide, metoprolol, certain statins, ondansetron, and several NSAIDs. The genetic test was performed for a specific indication, and the results can later be used to guide treatment with other medications. This means that the existing genetic result is being used for another purpose, rather than serving as a separate reason to order the test.

Some Spanish centers use panels that simultaneously analyze several pharmacogenes so that even when a pharmacogenetic marker is requested for a specific treatment, information on other pharmacogenes relevant to treatments the patient may receive now or in the future can also be obtained. However, using this additional information presents challenges, including the complexity of processing the data, difficulty of storing it in electronic health records, and differences in electronic health record management systems across the country. As a result, most centers currently do not interpret, store, or use additional pharmacogenetic information for other treatments.[

Pharmacogenetics has begun to be implemented in the NHS, but its use is likely to vary across hospitals, specialty care, and primary care. Proper interpretation, storage, and integration of pharmacogenetic data into electronic health records could help address this gap by making the information available to all healthcare professionals when prescribing medications. This remains one of the main challenges in improving the quality of care and patient safety through the reduction of adverse effects and more effective treatment selection and response.

The authors reported having no relevant conflicts of interest.

Susana Almenara and Francisco Abad Santos work in the Clinical Pharmacology Unit/Service at La Princesa University Hospital, Madrid, and Abad Santos also holds a post in the Department of Pharmacology at the School of Medicine, Autonomous University of Madrid, Spain.

This article was produced through an editorial collaboration between the Spanish Society of Clinical Pharmacology and Univadis Spain, part of the Medscape Professional Network.

This 2021 Sci Adv publication [see attached pdf file] was overlooked 5 years ago, when originally published, until Dave Eaton (Prof Emeritus, U Wash, Seattle) recently sent it to me. Does this topic “qualify” as GEITP’s “gene-environment interactions” theme? The answer is YES. All living organisms (including the developing embryo) are constantly challenged with the onslaught of undesirable adverse environmental signals, many of which damage the organism’s cells — ultimately contributing to the process of aging (in the developing embryo, the source of this adversity would be almost exclusively from metabolism — causing oxidative stress). On the other side, living cells contain numerous “anti-aging” mechanisms that attempt to block this onslaught and/or to repair the damage. In summary, “aging” vs “anti-aging” stimuli are certainly qualified as having a “gene-environment interactions” theme.

The trait being studied here is “aging” or “biological age” in the developing embryo. Aging can be considered a human complex disease — reflecting the combination of genes and the environment; in other words, there is a multiplex genetic component to this trait that is likely influenced by multiple environmental factors.

Unlike a monogenic (Mendelian) simple (dominant or recessive) trait that is mostly the manifestation of a single gene — human complex diseases (i.e., phenotypes) are usually multifactorial quantitative traits, influenced by [a] numerous small-effect variants of genes (alterations in DNA sequence); [b] epigenetic effects (DNA methylation, RNA interference, histone modifications, and chromatin remodeling); [c] environmental factors (smoking, occupation, lifestyle); [d] endogenous influences (ancestral differences, diseases of e.g., heart, lung, kidney, brain, etc.); and [e] each person’s unique microbiome.

The “environmental effects” being studied herein would be “factors in the in utero environment.” How many genes responding to these factors might be involved? As one dramatic example, studies on the multifactorial quantitative trait “height” have identified more than 12,000 small-effect genetic variants linked to height — which explain 10% to 40% of the variability in human height, depending on ancestry. “Biological age in utero” might also be considered as “subtle alterations in the patient’s genomic architecture.” “Genomic architecture” refers to random organization of functional elements (e.g., genes and regulatory regions) within the genome; i.e., it’s not just a linear sequence, but also includes the 3-dimensional arrangement of chromosomes and DNA in the nucleus, affecting how genes are expressed, how they are regulated, and how cells function.

Now that we have reviewed gene-environment interactions, let’s turn to this study about “biological age” (see attached pdf file). The notion that the germ line does not age goes back to the 19th-century ideas of August Weismann. However, being metabolically active, the germ line actually does accumulate damage and other changes over time, i.e., it ages. For new life to begin in the same young state, the germ line apparently must be rejuvenated in the offspring. Authors [see attached] developed a multi-tissue epigenetic clock and applied it, together with other aging clocks — to track changes in biological age during mouse and human prenatal development.

“Aging” can be (sort of) quantified by the progressive accumulation of damage, leading to the loss of physiological integrity, impaired function, and increased vulnerability to death. Whereas the aging process affects the entire organism, it is often discussed that the germ line does not age — because this lineage is presumably immortal in the sense that the germ line has reproduced indefinitely since the beginning of life of the organism. However, being in the metabolically active state for two decades or more before its contribution to the offspring, the human germ line accumulates molecular damage, such as modified long-lived proteins, epimutations, metabolic by-products, and other age-related deleterious changes [an “epimutation” changes how genes are expressed without altering the DNA sequence, whereas a “de novo mutation” is a brand-new, physical change in the DNA sequence. Epimutations are therefore potentially reversible, whereas genetic mutations are permanent].

It has been shown that sperm cells exhibit a distinct pattern of age-associated changes. Accordingly, it was recently proposed that germline cells might age, but then “can be rejuvenated” in the offspring after conception. If this is the case, there must be a point (or period of time) of the lowest biological age (herein, referred to as “ground zero”) during the initial phases of embryogenesis (see Fig. 1A of attached). Herein, the authors carried out a quantitative, data-driven test of this idea.

[I must admit: I had NEVER BEFORE heard about this proposed “rejuvenation effect.”] ☹☹

Because of recent advances in technology, machine learning is flourishing and has led to breakthroughs in many areas of science by discovering multivariate relationships. Aging and developmental-biology areas have also exploited the potential of machine learning — by developing algorithms (“aging clocks”) that can estimate chronological age or biological age (i.e., the age based on molecular markers) of an organism from a given dataset. Because epigenomic changes, which result in dysregulation of transcriptional and chromatin networks, are crucial components of aging, epigenetic clocks, based on methylation levels of certain CpG sites, have emerged as a promising molecular estimator of biological age. (“CpG islands” are specific regions of DNA with a high frequency of CpG sites (where a cytosine nucleotide is followed by a guanine nucleotide, with a phosphate bond in between); they are primarily found in vertebrate genomes and typically are located at the 5′ end of genes (the promoter region), acting as vital switches for gene expression.) These clocks have been shown to quantitatively measure numerous aspects of human aging. For example, epigenetic age acceleration has been associated with age-related conditions, such as all-cause mortality, cognitive performance, frailty, Parkinson disease, Down syndrome, and Werner syndrome.

Epigenetic aging clocks have also been developed in mice and can be used to evaluate longevity interventions (such as calorie restriction in growth hormone receptor knockout mice). The clocks developed on the basis of aging patterns of mostly adult tissues correctly predict much younger ages and report the effects of cell rejuvenation upon complete or partial reprogramming of adult fibroblasts into induced pluripotent stem cells (iPSCs) — as demonstrated in both human and mouse. Although iPSCs correspond to an embryonic state and the transition to these cells involves major molecular changes, including changes in the epigenome, this rejuvenation event can be assessed by epigenetic clocks. Most recently, universal mammalian clocks have been developed on the basis of conserved cytosines, whose methylation levels change with age across mammalian species.

Considering that epigenetic clocks can track the aging process, these clocks may be applied to embryos during early development to characterize biological age dynamics during that period of life. Recent studies have shown that clocks may be successfully applied to human fetal development using brain, retina, and cord blood samples [Genome Res. 2015; 25: 338–352. Genome Biol. 2016; 17: 206. Sci. Rep. 2019; 9: 3770.]. However, epigenetic age

dynamics during the entire prenatal development for the entire organism has remained unexplored. Until now. In the attached pdf file, authors developed a new multi-tissue epigenetic clock using machine learning and applied it, together with other existing aging clocks, to assess prenatal development in mammals from the perspective of aging. This approach has uncovered a rejuvenation period during early embryogenesis, and the timing of the beginning of aging in mammals…!!

The authors developed a multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, (i.e., rejuvenation), during early stages of embryogenesis, followed by an increase in later stages. Authors furthermore found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal aging.

In conclusion, the authors’ analysis revealed a significant decrease in biological age, i.e., rejuvenation, during early stages of embryogenesis (this is viewed as “aging”), followed by an increase in later stages. Moreover, authors found that pluripotent stem cells do not age — even after extensive passaging — and that the examined epigenetic age dynamics is conserved across species (mouse and human). Overall, this study uncovers a fascinating natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of actual “organismal aging.” 😊 GEITP cannot yet grasp our mind around this concept — nor can we conjure up any feasible REASON for Mother Nature to have developed such a system during evolution on this planet. ☹☹

DwN

Sci Advanc. 25 Jun 2021; 7(26): eabg6082. doi: 10.1126/sciadv.abg6082.