REPRODUCTIVE GENETICS

Trying to alternate the themes of our postings, we today offer a wider spread of subjects than usual. While starting with recent publications in genetics (in following the literature, it sometimes feels that almost everything in medicine is becoming “genetics”), we then clinically advance into immunology and especially into autoimmunity which has a special affinity with reproduction because self-tolerance and pregnancy are both at their basis dependent of normal development of immunological tolerance and, ultimately, into infectious diseases. And today’s posting ends with a brief article of a mother who lost her young son to a many years-long fight with two independent cancers very well covered by her job’s group health insurance. Yet years after her son’s death, the insurance industry, still, punishes her employer with higher insurance premiums. And she doesn’t like it on a very personal level!

The CHR’s Editorial Staff

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WE ARE ALL MOSAIC – The Huge Genetic Diversity in Cells of At Least Older Individuals

In what Heidi Ledford in a News article in Nature magazine described as a “technical tour de force,” a preprint on bioRxiv reported that researchers sequenced the whole genome of more than 100 individual cells from one 74-year-old male.² What they found was – as she put it - pure chaos: extra chromosome arms, chromosome deletions, smaller snippets of DNA altered, deleted or duplicated. Several cells had no Y chromosome left. In short, - nothing new – it’s is not great getting old.

As the article noted, this is the beginning of a new pilot project for a $140-million project of a consortium of investigators who aim to catalogue mutations in cells from 19 sites in the body using cells from 150 donors.

REFERENCES

1. Ledford H. Nature 2025;648:18

2. Luquette et al., Preprint at bioRxiv. 2025. https://doi.org/10.1101/225.10.31.685648

Sex Differences in the Genetics of Depression

We would say – unsurprisingly – a recent comprehensive genome analysis suggested that women have more genetic risk variants for major depression than do men, and they appear strongly linked to metabolic traits.¹ These findings were unsurprising for us because major depressive disorder (MDD) affects almost twice as many women as men. The biological reasons for this disparity are, however, unknown. Are they, for example, genetic or environmental (or both)?

Above noted study was a meta-analysis of genome-wide association studies (GWASs) — an approach for finding links between genetic variations and observable traits — that included almost 200,000 men and women with MDD. And here is just a little of what they found: Roughly 13,200 causal variants linked to MMD in women and only ca. 7,100 in men, with the latter all shared with women. This suggests that ca. 6,100 variants are exclusively linked to women. In addition the investigation also found three genomic regions with significant effects on MDD in women only, strongly suggesting sex-specific effects.

When the authors then examined genetic correlations – how genetic effects on one trait also relate to another trait, they discovered the much closer association of women than men with metabolic traits (i.e. BMI and metabolic syndrome), which fits with women having metabolic symptoms more frequently than men.

The study revealed several other interesting differences, but further details would exceed our allotted space here. The study is in detail explained in an article in the mothership of Nature journals, Nature by Na Cai, PhD from the Department of Biosystems and Engineering at ETH Zürich in Basel, Switzerland.²

REFERENCES

1. Thomas et al., Nat Commun.2025;16:7960

2. Cai N. nature 2025;647:600-601

We Soon Will Be Able to Transfer Chromosomes In and Out of Cells

This is a promising story because making human genomes has very obviously the potential to transform biology and – with it – human medicine. Now a group of investigators from all over Europe took a first important step in realizing this pipedream of building synthetic human chromosomes.¹

They developed a method to transfer a human chromosome into specialized “assembly” cells which allowed them to safely manipulate the chromosome. The so engineered chromosome then can be used with minimal genetic damage to replace a corresponding human chromosome in targeted human cells. True Science Fiction!

REFERENCE

1. Petris et al., Science 2025;390(6777):1038-1043

A New Dominantly Inherited Mutation Causing Female Infertility Because of Embryo Arrest at Preimplantation Stages

Embryo arrest at preimplantation stages is a quite common cause of female infertility and is frequently experienced in IVF cycles. Though various mutations have been implicated in causing arrest, most of its genetic basis is still unknown.

Geminin, encoded by the GMNN gene, plays an important role in preventing DNA re-replication by inhibiting CDT1. Here, using whole-exome sequencing and Sanger sequencing, the authors identified three rare missense mutations of the GMNN gene in females with preimplantation arrest. The mutation follows a dominant inheritance pattern.

RNA sequencing data from mouse zygotes and a patient’s one-cell embryo demonstrated altered cell cycle processes. The investigators then found that these mutations decreased the binding with CDT1 and resulted in activation of CHK1 as well as DNA damage, resulting in cell cycle disturbances.

As the authors summarized their paper, their findings uncovered a mechanistic explanation for some cases of human preimplantation-stage embryo arrest, which acts by impairing the correct cell cycle and DNA re-replication procedure. This discovery potentially offers a new molecular target for the diagnosis and treatment of some infertile women.

REFERENCE

1. Zhang et al., Sci China Life Sci 2025 68(8):2420-2430

INFECTIOUS DISEASES AND IMMUNOLOGY FOR REPRODUCTION

All Kind of Progress in the Treatment of Autoimmune Diseases

No other disease group has as close a physiological relationship with pregnancy as autoimmune diseases. A revolution is underway in the treatment of several autoimmune diseases with hope of curing the disease rather than just temporarily suppressing it. These new treatments were several years ago successfully introduced into cancer therapy and involve manipulations of the patient’s immune system via so-called CAR-T cells which, in the case of autoimmune diseases, have the ability to attack and eliminate autoreactive lymphocytes responsible for autoimmunity.

We here want to present two recent papers which demonstrated these new applications of CAR-T cell therapy in autoimmune diseases: Both are products of multicenter studies in China, both were accepted for publication within weeks from each other, published together in sequence in the same issue of Nature Medicine, and both reported on treatments with CAR-T cells in treatment refractory systemic lupus erythematosus (SLE).^1,2

PAPER 1 -- The first paper was a phase 1 trial using allogeneic CD-19-targeting T cells for treatment, while in the second paper autologous CD-19- and BCMA were targeted. Let’s start with the first paper by Wang et al.:¹

et al. In this paper the authors remind readers that CAR-T cell treatments (i.e., to spell it out, - commercial autologous anti-CD19 chimeric antigen receptor-T cell therapies) have been demonstrated to be effective in B cell malignancies several years before being used (and shown effective) in autoimmune diseases. The use of these calls is, however, still limited by the requirement for individualized personalized manufacturing at high costs and potential risks from random chimeric antigen receptor insertion into the genome.

To overcome these challenges, the authors of this study developed YTS109, a hypo immune allogeneic T cell product engineered using CRISPR–Cas9 to knock out TRAC, PD1, HLA-A, HLA-B and CIITA, with a CD19-targeting synthetic TCR and antigen receptor (STAR) precisely integrated into the TRAC locus to enable physiological, TCR-like signaling.

The article then reported on five patients with severe, refractory SLE complicated by lupus nephritis, who received lymphodepletion followed by YTS109 at 3 × 10⁶ STAR⁺ T cells per kg body weight. Primary endpoints were safety and SLE responder index 4 at month 3. Secondary endpoints included clinical remission and quality-of-life outcomes through to month 6.

YTS109 was well tolerated, causing only mild cytokine release syndrome but no graft-versus-host disease. All five patients achieved SLE responder index 4 responses by month 3, - sustained through to month 6. 4/5 patients showed rapid reduction in disease activity score (mean 31.30–5.35 by month 6), while one patient showed a mild refractory flare-up at month 6. Renal biopsies confirmed resolution of inflammation and tissue restoration, - unquestionably very promising results.

PAPER 2 – The second paper showed in a similar group of refractory SLE patients that peripheral CD19^⁺ B cells and bone marrow CD19⁻ B cell maturation antigen (BCMA)⁺ long-lived plasma cells are dominant sources of pathogenic autoantibodies, offering – in contrast to the 1^st paper -a strong rational for dual CD19 as well as BCMA targeting.²

The authors of this paper then report results from 15 patients (14 female, one male) in an ongoing phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA CAR T cells after fludarabine/ cyclophosphamide lymphodepletion.

Primary endpoints of these studies were dose-limiting toxicities (DLTs) within 28 days and adverse events within 12 weeks; key secondary endpoints comprised attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory endpoints were the duration of post-infusion B cell depletion and time to recovery, the kinetics of immune reconstitution and longitudinal changes in autoantibody titers and serum immunoglobulin concentrations after CAR-T cell therapy.

Over a median 712-day follow-up (range, 613–1,134), no DLTs occurred. Grade 1 cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity or treatment-related deaths. The most common grade 3 or higher adverse events were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which were reversible with supportive care.

By week 12, 12 of 15 patients (80%) fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive IgM/IgD B cells and durable downregulation of interferon-stimulated and BAFF-dependent signatures, indicating improved immune homeostasis.

Longitudinal monitoring of three patients for 1 year demonstrated sustained eradication of pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T cell therapy, thus, demonstrates good safety and promising clinical efficacy in treatment-refractory SLE and, therefore, supports the further development of this treatment approach.

With publication of these two papers, the two groups of Chinese investigators, moreover, repeated the pioneering involvement in the early days of CAR-T cell therapy in primarily liquid cancers. Truly remarkable work which, - as noted earlier – offers hope for the cure of autoimmune diseases like SLE, - but also offers a clearly better understanding of how abnormal immune system antibody responses may be corrected and/or even prevented, which may have relevance not only for the treatments of abnormalities in self-tolerance but mal- sometimes in the future – also be applicable to the treatment of abnormal tolerance toward the fetal-placental semi- or complete allograft.

VAGUS NERVE STIMULATION -- Completely unrelated to CAR-T cell therapies, another new treatment approach for autoimmune diseases has recently made headlines, - vagus nerve stimulation (VNS). Yes, and if you don’t believe us, the FDA just approved VNS as treatment in rheumatoid arthritis (RA), - in a recent Healio article described as yet another “paradigm shift” in autoimmunity, especially in cases of rheumatoid arthritis.³ Before approval for RA, vagal nerve stimulation was already FDA-approved for the treatment of epilepsy, treatment-resistant depression, and during stroke rehabilitation.

The driving force behind the approval for RA was Kevin J. Tracey, MD, president and CEO of the Northwell Health’s Feinstein Institute for Medical Research (we, indeed, were privy to hear about vagal stimulation at a GrandRounds lecture at the CHR over two years ago).

Kevin J. Tracey, MD

According to a recent Healio article studies of vagus nerve stimulation are currently considered for multiple sclerosis, inflammatory bowel disease, psoriasis, and spondyloarthritis.

FDA approval was apparently based on a double-blind, placebo-controlled study in which patients over 12 weeks daily underwent 60 seconds of vagus nerve stimulation which produced significantly improved ACR response outcomes over placebo treatments (P=0.0209). The difference was even more pronounced in patients with one prior treatment episode with either a biological or a traditional anti-rheumatic drug (P= 0.0054). The article quoted an Arizona-based rheumatologist as noting that “it would seem that almost any of our diseases where inflammation is driving the condition could benefit from these techniques.”

But who needs implanted devices? There supposedly is no better vagal stimulation than an ice plunge!

REFERENCES

1. Wang et al., Nat Med 2025; 31:3713-3724.

2. Feng et al., Nat Med 2025;31:3725-3736

3. Healio. November 14, 2025. https://www.healio.com/news/rheumatology/20251113/approval-of-vagus-nerve-stimulator-may-herald-pivot-point-for-rheumatology

Important News from the World of Infectious Diseases

SEVERE FLU SEASON – It’s a pretty bad flu season this year and not only for the older population. The yearly vaccine missed the currently dominant strain when the vaccine was designed because the strain wasn’t around then (or at least wasn’t recognized to be around). From that follows that this year’s flu vaccine is not very effective in preventing disease; but it, still, is quite effective in preventing severe disease, including the need for hospitalization.

The CHR, therefore, strongly recommended that infertile women in treatment and/or already pregnant women get vaccinated. Remember, like COVID-19 was more severe in pregnant women, so is the flu! This also corresponds to recommendations from various professional societies, including ACOG.²

Here is a quick summary of the CDC’s weekly U.S. Influenza Surveillance Report Update for week 52 which ended on December 27, 2025, and was published on January 5, 2026.¹ Outpatient Illness

8.2% (Trend ↑ )
of visits to a health care provider this week
were for respiratory illness
(above baseline).

28.1 cumulative hospitalization rate per
100,000 population

31.3 (Trend ↑ ) weekly hospitalization rate
per 100,000 residents

33,301 (Trend ↑) patients admitted to hospitals
with influenza this week.

0.9% (Trend ↑) of deaths attributed to
influenza this week

A first influenza-associated death occurring
during the 2025-26 season was reported.³

The CDC estimated that by January 5, 2026, there have been at least 11,000,000 illnesses, 120,000 hospitalizations, and 5,000 deaths from the flu so far this season.

REFERENCES

1. CDC, Flu View., January 5, 2026. https://www.cdc.gov/fluview/surveillance/2025-week-52.html

2. ACOG Digest, December 3, 2025. Accessed December 5, 2025

3. Taylor L. BMJ. November 24, 2025; 391. Doi: https://doi.org/10.1136/bmjr2480

COVID-19 and the Flu May Reawaken Dormant cancer cells

A Medical News article in JAMA Medical News recently discussed a new finding that respiratory viral infections can trigger the proliferation of dormant breast cancer cells in the lungs.¹ That cancer-mortality had increased during COVID-19 has been known for quite some time; but the explanation widely accepted for this finding – that the pandemic interfered with timely diagnosis and treatments – was apparently wrong or at least partially incorrect.

The person who suspected that the SARS-CoV-2 virus may play a role was a professor of intensive care medicine at the University College London, who’s sister – after being declared breast cancer free – she while on holidays was likely infected with COVID-19. Because of symptoms, she had a chest x-ray that revealed what proved to be metastatic spread form her supposedly cured breast cancer. She died five months later.

Deciding to investigate the issue with some colleagues, the research started in a mouse model and with a closer look at epidemiological data and here is what the investigators found as reported in Nature: They demonstrated, in mice, that influenza and SARS-CoV-2 infections lead to loss of the pro-dormancy phenotype in breast DCCs in the lung, causing dormant disseminated cancer cell (DCC) proliferation within days of infection and expanding carcinoma cells massively within two weeks into metastatic lesions.

These phenotypic transitions and expansions are, moreover, IL-6 dependent. These DCCs also impaired lung T cell activation. CD4⁺ T cells sustained the pulmonary metastatic burden after the influenza infection by inhibiting CD8⁺ T cell activation and cytotoxicity.

These experimental findings then also aligned with the originally suspected human observational data (including in the physician’s sister): An analyses of cancer survivors from the UK Biobank (all kinds of cancers) and Flatiron Health (breast cancer only) databases revealed that SARS-CoV-2 infection substantially increases the risk of cancer-related mortality and lung metastases compared with uninfected cancer survivors. These discoveries underscore the huge impact of respiratory viral infections on metastatic cancer resurgence and – as the authors noted – offer new insights into the connection between infectious diseases and cancers.

REFERENCE

1. Anderer S. JAMA Medical News 2025;334(12):1047-1048

Long COVID, - the Problem That Does Not Go Away

This condition can affect the wellbeing of individuals post-COVID for months or even years and no satisfactory treatment has yet been discovered. The condition, therefore, is in symptomatology similar to other chronic post-infection syndromes.

A recent paper in Nature Immunology by Boston investigators now shed some new light on the condition. Performing immunological, virological, transcriptomic and proteomic analyses from a cohort of 142 individuals between 2020 and 2021, including uninfected controls (n = 35), acutely infected individuals (n = 54), convalescent controls (n = 24) and patients with long COVID (LC, n = 28).

What they found was that the LC group was characterized by persistent immune activation and proinflammatory responses for more than 180 days after initial infection compared with convalescent controls, including upregulation of JAK-STAT, interleukin-6, complement, metabolism and T cell exhaustion pathways. Similar findings were observed in a second cohort enrolled between 2023 and 2024, including convalescent controls (n = 20) and patients with LC (n = 18).

The authors correctly concluded that these data may suggest that LC is characterized by persistent activation of chronic inflammatory pathways, which can suggest new therapeutic targets and potential biomarkers for this diagnosis.

REFERENCE

1. Aid et al., Nat Immunol 2026; 27:61-71

Epstein-Barr Virus – Often Accused but Only Rarely Convicted

As the Editor’s Summary for this article of Westcoast investigators in Science Translational Medicine appropriately summarized, - the Epstein-Barr virus (EBV) has been accused of many crimes, including the accusation that it is a candidate driver of autoimmune diseases like multiple sclerosis and of long post-viral diseases like long COVID.¹

What makes this study so interesting is some evidence this study offers that where there is smoke, there may also be fire because the authors demonstrate a link between EBV infection and later disease development. By identifying EBV-infected cells by RNA sequencing, they were able to demonstrate distinct differences between infected and uninfected B cells.

EBV-infected B cells develop antigen-presenting ability and were capable of activating autoreactive helper T cells which could activate other B cells and that included uninfected B cells (confirmed by in vitro studies). At least in association with systemic lupus erythematosus (SLE), it appears that the EBV can infect and reprogram autoreactive B cells which then , in turn, can drive a systemic autoimmune response in SLE.

Now the question is which other autoimmune diseases can be initiated by the EBV (or similarly functioning viruses)?

REFERENCE

1. Younis et al., Sci Transl Med 2025. DOI. 10.1126/scitranslmed.ady0210

A CITIZEN’S TRULY HEART-FELT BELIEVE ABOUT THE COUNTRY’S HEALTH INSURANCE BUSINESS

When Illness Outlives the Patient

This brief article reflects the feelings of Jolanta Tapper, the CHR’s Chief Operating Officer who lost her son to cancer.

In the United States, laws such as the Affordable Care Act were designed to protect individuals from discrimination based on medical history. These protections aim to ensure that families facing serious illnesses are not denied coverage or treated unfairly simply because they needed care. Yet, real-world insurance practices can still produce outcomes that feel at odds with that promise.

Consider a family whose child spent years battling cancer while covered under a parent’s employer-sponsored group health plan. During that time, the family and their employer did what the system expects: they relied on insurance to cover necessary, life-saving treatments. Tragically, the child passed away in January 2022, leaving the family to cope with profound loss.

Years later, the story takes an unexpected turn. The employer—like many businesses—shops for more affordable coverage during a renewal period. Despite the passage of time and the absence of ongoing high-cost claims, insurers – as it turns out - still view the group as higher risk due to the child’s past cancer treatment. The case, though rare and no longer generating expenses, remains part of the group’s claims history.

As a result, the company now faces significantly increased insurance costs for all employees. In some cases, access to more competitive or lower-cost plans may even be limited. What was once a necessary effort to save a child’s life continues to influence financial outcomes years later—not just for the family, but for an entire workforce.

This situation highlights a lesser-known aspect of the insurance system. While individual protections under federal law prevent denial of coverage due to pre-existing conditions, employer-sponsored group plans—especially those that are experience-rated—can still be influenced by past claims. High-cost cases, even when resolved and no longer active, may affect how insurers assess risk and price coverage.

For the affected family, the emotional weight is obvious. But there is also a broader impact: colleagues and employers, removed from the original tragedy, now share in its financial ripple effects. This can create tension, confusion, and a sense that the system is assigning long-term consequences to events that are both rare and beyond anyone’s control.

At its core, this raises an important question about fairness. Insurance is designed to spread risk, not concentrate it indefinitely on specific individuals or groups based on past hardship. When a single, resolved medical event continues to shape costs years later, it challenges whether that balance is being upheld.

Families who fought to save a child should not remain defined by that fight. And employers who provided coverage during a time of crisis should not face prolonged penalties for doing so.

If the impact of a child’s illness can persist long after both the treatment and the life it sought to save have ended, it forces a difficult but necessary question: is the system truly functioning as a safety net—or has it allowed past tragedy to become an ongoing liability?

You tell us!