Edward Nirenberg
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enirenberg.bsky.social
Edward Nirenberg
@enirenberg.bsky.social
24K followers 8.3K following 6.5K posts
Views my own, but you can borrow them if you feel so inclined. Anti-disease. Negentropy hunter. Kosmotropophile. Big Nerd Energy. “A homework person.” Fun at parties. Antibody hoarder. “Problematically literate.” he/him
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enirenberg.bsky.social
I find this question odd. Creativity IMO is a statement about the process more than the outcome. I don't think it's simply about innovation. Insofar as there is no cognition involved here (we're basically dealing with a very fancy autocorrect), it's axiomatically not possible for AI to be creative.
Can AI truly be creative?
November 5, 2025 at 7:30 PM
enirenberg.bsky.social
PSA: It is very difficult to do chest auscultation when the stethoscope earpieces are not in your ears.
A stock photo (or possibly AI-generated) showing a physician with a stethoscope bell placed on the chest of a young girl in a pediatric patient gown. The stethoscope earpieces are clearly not in his ears.
November 4, 2025 at 10:13 PM
enirenberg.bsky.social
I don't think I've ever seen a lymphocyte gate quite like this one
flow cytometry plot showing a polygon covering essentially everything except for the highest side scatter cells and labeling all of them lymphocytes
October 30, 2025 at 9:05 PM
enirenberg.bsky.social
Oh—forgot to include this; this is the author's proposed mechanism for how this is occurring
Proposed mechanism of action by which mRNA vaccines might enhance the immune response to tumors. Initially, we have a cold tumor (one with minimal T cell infiltration). We administer an mRNA vaccine and trigger a surge of type 1 interferon. This leads to activation of professional antigen-presenting cells that can now go on to recruit T cells to participate in the immune response against the mRNA vaccine. This also results in increased expression of PD-L1 within the tumor. If we then throw in ICI therapy against PD-1 or PD-L1, that mechanism is not able to suppress T cell responses, leading to the eradication of the tumor.
October 25, 2025 at 6:11 PM
enirenberg.bsky.social
But, the fact that the team examined this question across so many different angles and consistently found support no matter how they looked is IMO quite compelling for this being a real effect of mRNA vaccines.

There's also this note from the paper:
As personalized neoantigen vaccines require considerable manufacturing time, off-the-shelf RNA-LNPs targeting tumour-associated or even infectious disease antigens may represent widely available, low-cost alternatives for patients waiting for personalized neoantigen vaccines or in settings in which personalized neoantigen vaccines are not available.
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
They used a large cohort of tumors from biopsies of non-small cell lung cancer and stratified by receipt of mRNA vaccine at ≤ 100 days, > 100 days, and no mRNA vaccine. It turns out that mRNA vaccination within 100 days was associated with greater TPS scores. And...
b- TPS levels by receipt of mRNA vaccine (none, within 100 days, within more than 100 days) finds that there is more PD-L1 expression for recent mRNA vaccination. c- TPS >50% was most likely to occur in those who received an mRNA vaccine within 100 days. d- effect of influenza vaccination on TPS (none) e- effect of pneumonia vaccination on TPS (none) Overall survival plots: j- Survival of patients in i stratified by receipt of COVID-19 vaccine before ICI k- Survival for patients in the tissue-agnostic cohort treated with ICI who started ICI in the pandemic era (since 2 September 2020, 100 days before mRNA vaccine approval). l- Survival of stage IV NSCLC with TPS <1% m- Survival of stage IV NSCLC with TPS >1% and ≤49.9% n- Survival of stage IV NSCLC with TPS >50% o- Survival of stage IV NSCLC with TPS <1% comparing pandemic and pre-pandemic era survival in those who did not receive mRNA vaccines In all cases, mRNA vaccination associated with superior overall survival.
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
But... Moderna gave much higher levels of type 1 interferon than Pfizer. Whether this makes a difference clinically is not yet known.

Next the team wanted to look at human cancers to see whether mRNA vaccines boosted PD-L1 expression (quantified as a tumor proportion score, TPS, a percentage).
Relative fold-increases in cytokines comparing Pfizer to Moderna (larger values indicate greater levels of induction for Moderna than Pfizer).
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
Are these mice lying? Well, we can't really graft tumors onto humans and give them these treatments to compare what happens for ethical reasons, but we can do the next best thing—we can see whether the pattern of the immune response to mRNA vaccines is similar between mice and humans. They are!
Healthy volunteers received COVID-19 mRNA vaccines and had serial blood draws at 6 hours, 24 hours, 7 days, and 14 days from 5 health individuals. There was a drastic enhancement of type 1 interferon levels seen in the blood at 24 hours post-vaccination for all individuals. By 7 days, the levels returned to near baseline. In addition to this, PD-L1 expression on circulating myeloid cells (which activate T cells) also peaked at 24 hours. CD25 (a receptor for the cytokine IL-2) was also greatest at 24 hours and then returned to baseline by 7 days after vaccination.
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
How is it doing this? The team showed that the combination of both therapies resulted in markedly better activation of killer T cells and increased tumor expression of PD-L1, the target of ICI. This is likely the key enabling condition for the effect on tumors observed with mRNA+ICI because...
a-c: CD8 effector T cells and CD8 effector memory T cells were most robustly induced by ICI+mRNA vaccine. This group also showed the highest responsiveness to the melanoma-associated antigens survivin, GP100 KVP, GP100 EGS, WT1, and TRP2. d. Activation assay of T cells to tumor antigens shows drastically higher activation of T cells for the ICI+mRNA group, which is lost when type 1 interferon signaling is blocked. e-g: representative histology showing that ICI+mRNA results in the greatest expression of PD-1 (found on T cells) in the tumor and quantification of PD-1 expression in the tumor and on CD8 T cells specifically (also showing ICI+mRNA produces the greatest level of PD-1 expression). h. There is markedly better induction of killer T cells responsive to melanoma antigens with ICI+mRNA (though it is pretty similar to mRNA alone). i-k: mRNA vaccine + ICI drastically increases tumor expression of PD-L1 (the binding target for PD-1 on T cells that tells them not to respond—a process that ICIs block to enable tumor eradication)
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
While not definitive, exploring potential mechanisms in animals can help. The team got some mice, gave them some very aggressive tumors, gave them ICIs, and gave them mRNA vaccines (or didn't). Here's what happened there:

Here, mRNA vaccines stall tumor growth in mice, and mRNA+ICI do even better.
a-d: schedules of receiving mRNA vaccine relative to other interventions and the effect on tumor size. One of the most interesting consistent findings is that while mRNA vaccine + immunotherapy show the strongest effect in delaying tumor growth across all tumor types and schedules, the mRNA vaccine alone seems to have a stronger effect on preventing tumor growth than immunotherapy does. Importantly, while blocking the cytokine IL-1 showed no effect on tumor growth, blocking signaling by type 1 interferon abolished the effect on tumor growth suppression, meaning this effect is mediated by type 1 interferon. e-i: various immunological parameters quantified across groups. The mRNA and mRNA+ immunotherapy groups show much more active immune responses than immunotherapy alone or immunotherapy + empty lipid nanoparticle of mRNA vaccines. Of particular importance: the level of type 1 interferon is much, much higher with mRNA vaccine groups. j-o: comparison of untreated vs mRNA vaccine + immunotherapy in the ability of cells in the spleen to become activated. In all cases, receipt of the mRNA vaccine + immunotherapy is drastically higher. The mRNA vaccines available for COVID-19 vaccination use a "modified" base called N1-methylpseudouridine (note that this base naturally occurs in our own ribosomal RNA) instead of uridine (U) to avoid early recognition of the mRNA by the innate immune system. If the innate immune system is tripped to early in the process, it will prevent the mRNA vaccine from effectively generating spike protein, which will leave the immune system lacking a target to develop memory against. The team asked whether using unmodified RNA (where uridine is used instead of N1-methylpseudouridine) would affect the tumor size because unmodified RNA produces a much stronger type 1 interferon response and the team showed that type 1 interferon induced by the mRNA vaccines accounted for the effect of mRNA vaccine on tumor growth. They explored the effect of an mRNA vaccine that encoded pp65, a protein from cytomegalovirus that's commonly overexpressed on human gliomas, as well as spike. There was slightly better suppression of tumor growth with the unmodified RNA for pp65, though this was not the case when the mRNA encoded the spike protein, in which there was no difference between modified and unmodified RNA. Cytokine responses to mRNA vaccine ± ICI and ICI with or without empty lipid nanoparticles without mRNA. Broadly, the induction of pro-inflammatory cytokines and chemokines was generally greatest for ICI+mRNA-LNP groups, with the exception of IL-6, which was highest for ICI + mRNA-LNP groups.
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
In short, people who got an mRNA vaccine within 100 days of starting their immunotherapy lived for nearly twice as long in this cohort, and had nearly double the likelihood of living 3 years. This effect was restricted to mRNA COVID-19 vaccines. The effect of Pfizer vs. Moderna was similar.
In brief, chemotherapy without immune checkpoint inhibition did not show a clear benefit of COVID-19 vaccination. However, flu vaccination did not demonstrate a benefit for survival nor did pneumonia (pneumococcal vaccination) even before correcting for immortal time bias. Importantly, when the NSCLC (non-small cell lung cancer) tumor was resectable, receipt of COVID-19 vaccines didn't have a significant effect on survival). Extended Data Fig. 2 | COVID mRNA vaccines are uniquely associated with improved survival in patients with NSCLC treated with ICI. a, Overall survival for NSCLC patients who did not receive immune checkpoint inhibition and received a COVID vaccine within 100 days of initiating chemotherapy or did not receive a COVID vaccine. b-e, Overall survival for NSCLC patients stratified by receipt of influenza vaccines (b-c), or pneumonia vaccines (d-e) with all events included (b, d) or, to correct for immortal time bias, including only events that occured greater than 100 days after initiating ICI (c, e). Patients who also received COVID vaccination were excluded from the influenza and pneumonia vaccine analyses. f-g, Overall survival for (f) all patients with Stage III NSCLC and (g) patients with Resectable Stage III NSCLC treated with ICI who received a COVID mRNA vaccine within 100 days of initiating ICI or did not receive a COVID mRNA vaccine. Hazard ratios and p values were calculated by log-rank (Mantel-Cox, two-sided) tests. a-Pfizer and Moderna show similar mortality curves for overall survival of patients. b. the specific dose the vaccine represented (prime, prime and boost, boost x1, and boost x 2) showed broadly similar results. c. receipt of 1 vs 2 vaccines also had a similar effect size on survival d. vaccination before starting ICI therapy showed a dramatic improvement in survival (HR, 95% CI: 0.34, 0.17-0.70) compared with no vaccination e. Pandemic era comparing receipt of COVID-19 mRNA vaccine vs no vaccine. Proportional hazards intersect g-k: mRNA vaccination was associated with improved outcomes across a wide variety of melanomas
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
The conversion of immunologically cold to immunologically hot tumors is a major area of interest within immuno-oncology:
doi.org/10.1016/j.it...

Enter: this study. First, the team saw that people who had an mRNA vaccine within 100 days of starting immunotherapy (ICI) survived longer.
Kaplan-Meier curves for survival based on receipt of mRNA vaccine or no vaccine according to tumor type and stage. Consistently, the vaccinees survived for longer. Fig. 1 | COVID-19 mRNA vaccines are associated with improved survival in patients with NSCLC or metastatic melanoma receiving immunotherapy. a–e, Survival for patients with NSCLC (a–c) or metastatic melanoma (d,e) treated with ICI who received a COVID-19 mRNA vaccine within 100 days of initiating ICI or did not receive a COVID-19 mRNA vaccine. Survival is shown for all patients with NSCLC (a), patients with unresectable stage III NSCLC (b), patients with stage IV NSCLC (c) and patients with metastatic melanoma (d and e). P values and HR adj were calculated using two-sided Cox proportional hazards regression (Supplementary Tables 3, 5, 7, 9 and 11), including all variables that were significantly associated with survival on univariable analysis (Supplementary Tables 2, 4, 6, 8 and 10). The number of patients at risk at each timepoint is indicated below each graph.
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
In the case of cancer, you want tumors to be "immunologically hot," meaning that there's lots of infiltration of immune cells (especially killer T cells) and they are highly activated. Unfortunately, many tumors are cold (immune desert, immune excluded)...

www.cell.com/immunity/pdf...
Coarse groupings of the patterns seen with tumor microenvironment. In the immune desert, the immune system simply cannot access the tumor at all. In the immune excluded situation, the cells of the immune system can access the tumor, but the tumor has immunosuppressive signals that block effective responses. The inflamed case is ideal for the eradication of tumors, wherein there is a highly active immune response within the tumor, including the formation of tertiary lymphoid structures (TLS). Untreated prostate cancer, colon cancer, and melanoma most often exhibit desert, excluded, and inflamed phenotypes, respectively. https://www.cell.com/immunity/pdf/S1074-7613(23)00416-8.pdf An overview of the cancer-immunity cycle. Initially, a cancer cell dies and releases antigens that the immune system can recognize and target. This leads to activation of professional antigen presenting cells, which go to the lymph node and find T cells that can recognize the cancer antigens, activating them. That leads those T cells to them migrate into the tumor and begin killing those cells. As this occurs, there may be establishment of tertiary lymphoid structures (basically, aggregates of immune cells similar to a lymph node that are really good at activating immune responses against the tumor) which maintain the killing activity of T cells to promote tumor eradication. Janeway's Immunology 9th Edition, Figure 16.13: When tumors appear, the immune system has a number of cells that can kill those cells. Tumors, however, are prone to mutate, and, eventually, you might get a variant cell that is resistant to killing. That cell can then proliferate to become a tumor resistant to eradication.
October 25, 2025 at 5:53 PM
enirenberg.bsky.social
Literally the most ridiculous grocery store on the planet.
Erewhon sells "Hyper Oxygenated Water" 64 oz $25.99 "This hyper oxygenated water is non-carbonated and offers a refreshing taste. It is made by the brand Ophora and contains natural ingredients. Perfect for staying hydrated throughout the day." Ingredients: Nano-purified, hyper-oxygenated water
October 18, 2025 at 5:09 AM
enirenberg.bsky.social
I can't decide whether I like or hate this new nomenclature.
IL-1 Family Cytokines New Name Primary Receptor(s) Co-receptor Function IL-1α IL-1F1 IL-1R1 IL-1R2 IL-1RAcP (IL-1R3) Inflammatory IL-1β IL-1F2 IL-1Ra IL-1F3 IL-1R1 Anti-inflammatory IL-18 IL-1F4 IL-18Rα (IL-1R5) IL-18Rβ (IL-1R7) Inflammatory IL-33 IL-1F11 ST2 (IL-1R4) IL-1RAcP (IL-1R3) Inflammatory IL-36α IL-1F6 IL-36R (IL-1R6) IL-1RAcP (IL-1R3) Inflammatory IL-36β IL-1F7 IL-36γ IL-1F8 IL-36Ra IL-1F5 Anti-inflammatory IL-37 IL-1F7 IL-18Rα (IL-1R5) IL-1R8 Anti-inflammatory IL-38 IL-1F10 IL-36R (IL-1R6) IL-1R9 Anti-inflammatory
October 9, 2025 at 9:06 AM
enirenberg.bsky.social
This year's Nobel Prize in Physiology or Medicine was just announced:
www.nobelprize.org/prizes/medic...

This seems like a good opportunity for me to explain a bit about peripheral immune tolerance and where the prizewinners' work comes in 🧵
6 October 2025 The Nobel Assembly at Karolinska Institutet has decided to award the 2025 Nobel Prize in Physiology or Medicine to: Mary E. Brunkow Institute for Systems Biology, Seattle, USA Fred Ramsdell Sonoma Biotherapeutics, San Francisco, USA Shimon Sakaguchi Osaka University, Osaka, Japan “for their discoveries concerning peripheral immune tolerance”
October 6, 2025 at 1:04 PM
enirenberg.bsky.social
Me explaining how adjuvants work to non-immunologists cc @druvbhagavan.bsky.social
Alum make APC [antigen-presenting cell]go boom. Injection site big mad. Antibody production go brrr
October 1, 2025 at 12:19 AM
enirenberg.bsky.social
You, in fact, do not, and if the goal is prevention of NTDs, you should not substitute folic acid with other folates regardless of MTHFR genotype.

www.cdc.gov/folic-acid/d...

www.gimjournal.org/article/S109...
Impact on your body's ability to process folate You may have heard that if you have an MTHFR variant, you should avoid folic acid and should take other types of folate, such as 5-MTHF. However, this is not true. People with an MTHFR gene variant can process all types of folate, including folic acid. Folic acid is the only type of folate shown to help prevent neural tube defects (NTDs).1 When getting the same amount of folic acid, people with the MTHFR 677 TT genotype have an average amount of folate in their blood that is only slightly lower (about 16% lower) than in people with the MTHFR CC genotype.5 Studies show that getting 400 mcg of folic acid daily can increase blood folate levels, regardless of your MTHFR genotype. Your folic acid intake is more important than your MTHFR genotype for determining the amount of folate in your blood.3567 There isn't enough evidence to show that the MTHFR A1298C variant alone significantly affects how the body processes folate. Common MTHFR variants, such as MTHFR C677T, are not a reason to avoid folic acid.
September 29, 2025 at 3:29 PM
enirenberg.bsky.social
Sure, but my understanding is that the consensus for how folic acid prevents NTDs is not known even if some mechanisms are proposed:
jamanetwork.com/journals/jam...
How Does Evidence Fit With Biological Understanding? Genetic predisposition and environmental influences are thought to contribute to neural tube defects. These environmental influences are being investigated. An important environmental influence is the consumption of folate. The mechanism of action of folate in the prevention of neural tube defects is unknown. Folate acts as a coenzyme in the synthesis of nucleic acids and the metabolism of amino acids.
September 29, 2025 at 4:27 AM
enirenberg.bsky.social
Wanna guess what happens if you do the adjustment? The association disappears.
jamanetwork.com/journals/jam...

Acetaminophen does not cause autism.
Results In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, −0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, −0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, −0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, −0.02% [95% CI, −0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, −0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively.
September 23, 2025 at 4:19 PM
enirenberg.bsky.social
I don't know whether this has been discussed by anyone yet, but the meta-analysis that claims to find a relationship between acetaminophen and autism: ehjournal.biomedcentral.com/articles/10....

Here's how it reported the results for the largest study. This study carries massive weight...
Authors, Year Location Study Period Risk Estimate Study Design Sample Size Missing Data Inclusion Criteria Exposure Definition Outcome Definition Ahlqvist, 2024 (overall study) Sweden 1995–2019 HR = 1.05 (95%CI 1.02–1.087) Prospective cohort N = 2,480,797 Exclusion and covariates imputed using dummy category approach All Singleton live born children in Sweden with linkable personal identifiers with follow-up until Dec 31,2021 Ever use APAP derived from midwife interview at 8–10 weeks gestation and later during pregnancy. From 2005 onward supplemented by Prescribed Drug Registry data Autism from ICD codes recorded in the National Patient Registry
September 23, 2025 at 4:19 PM
enirenberg.bsky.social
There's a great book for people who think like that
How To Avoid Vaccines And Die Like A Medieval Peasant By R. Kennedy
September 22, 2025 at 11:53 PM
enirenberg.bsky.social
Wanna know how to tell whoever is running the CDC has no clue what they're talking about?

It's "correlate of protection," not "correlative protection." h/t @malar0ne.bsky.social

In another era, this would be extremely embarrassing.
CDC @CDCgov ACIP member Robert W. Malone, MD: “There is no established correlative protection for COVID. Period. Full stop. And stop saying otherwise.”
September 20, 2025 at 12:06 AM
enirenberg.bsky.social
ACIP member Levi felt the need to remind us that he’s a professor at MIT.
ACIP COVID-19 IMMUNIZATION WG: INTRODUCTION Professor Retsef Levi, PhD, MIT
September 19, 2025 at 2:16 PM
enirenberg.bsky.social
This literally isn't even within ACIP's purview
Hepatitis B vaccine - Vote #1 All pregnant women should be tested for hepatitis B infection.
September 18, 2025 at 8:42 PM