Friday Roundup 4/7/2023

Some spring cleaning, more on AI including AI sitcoms, and the mRNA milk hysteria on social media.

Spring has sprung…ish

Well, it appears that it’s finally spring…sort of. It feels like the weather is continuously oscillating between typical February chills to June heat here. Unfortunately, it seems as if this has caused many flowers to bloom and turnover rather quickly, so there’s minimal enjoyment to be had in observing nature coming back to life.

But with spring comes a lot of so-called “spring cleaning”, or really “designated time of cleaning that could otherwise occur at other times of the year”.

In the next few days I’ll be doing some spring cleaning (as well as planting some herbs if the squirrels don’t get to them…), but not just my house, but also with this Substack.

That is, there’s a bit of organizing that needs to get done to make posts more searchable and better archived. That also includes making some anthology posts for things such as my microbiome post so that they are easier to share.

With that, if there are any sections that people may consider worthwhile to include in my reorganizing please let me know. I think making one about COVID, vaccines, and therapeutics will be helpful, but if there’s any other categories worth considering please let me know!

Unfortunately, this time is also… tax season! Nothing’s more scary than figuring out if the government took too much of your money or if the government wants more. 😭

So the posts may be sporadic within the following week (maybe…) given the above things going on.

AI in science and comedy

This is something that I should have done in hindsight of Tuesday’s post- I should have only included one of the abstracts and asked readers to guess whether the abstract was generated or the original. Silly me for remembering after-the-fact, as well as a thank you to Soulbee3 in the comment who helped me realize that I goofed on presenting the abstracts.

And for anyone interested, Soulbee3 appears to have compiled a pdf of JJ Couey’s hypothesis on SARS-COV2. I’ve never looked deeply into his (Couey’s) work but the layout and presentation may be very helpful for people who prefer a layman’s explanation for Couey’s hypothesis.

The Best Biological Sense

But to go back to the AI abstracts, I thought it would be fun to scramble around and provide some of those abstracts below for readers to determine whether they are generated or original abstracts.

Hopefully no one looked at the actual study from Tuesday (you didn’t, did you?) so let’s pretend that this presentation is absolutely the first time you are seeing these abstracts because you absolutely did not look at the study from Tuesday!

Note that the following abstracts are modified to remove some revealing information, and I will post the answers to these abstracts (whether original or generated) in the comments tomorrow as a pinned comment. Also, the polling will be kept secret until tomorrow so that they can’t influence your answer (well, hopefully that’s how it will go 🤷‍♂️).

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Abstract #1

“Association of COVID-19 Vaccinations With Intensive Care Unit Admissions and Outcome of Critically Ill Patients With COVID-19 Pneumonia in Lombardy, Italy”

Background

COVID-19 has had a significant impact on healthcare systems worldwide, leading to high rates of intensive care unit (ICU) admissions and mortality. Vaccines have been developed and deployed as a means to combat the pandemic, but their effect on critically ill patients with COVID-19 pneumonia remains unclear.

Objective

To determine the association of COVID-19 vaccinations with ICU admissions and outcomes in critically ill patients with COVID-19 pneumonia in Lombardy, Italy.

Design

Retrospective cohort study.

Setting

ICUs in Lombardy, Italy.

Participants

A total of 314 critically ill patients with COVID-19 pneumonia admitted to ICUs in Lombardy between January 1 and June 30, 2021.

Exposure

COVID-19 vaccination status.

Main Outcomes and Measures

The primary outcome was ICU admission, and secondary outcomes included ICU mortality and length of ICU stay.

Results

Of the 314 critically ill patients with COVID-19 pneumonia, 149 (47.5%) were vaccinated. The vaccinated group had a significantly lower rate of ICU admission compared with the unvaccinated group (47.0% vs 63.2%; difference, −16.2% [95% CI, −26.6% to −5.9%]; P = .002). In addition, vaccinated patients had a lower ICU mortality rate compared with unvaccinated patients (14.8% vs 25.0%; difference, −10.2% [95% CI, −20.8% to 0.3%]; P = .05). The length of ICU stay did not differ significantly between the vaccinated and unvaccinated groups (median, 8 days [interquartile range, 5-13 days] vs 9 days [interquartile range, 5-14 days]; P = .50).

Conclusions and Relevance

In this cohort of critically ill patients with COVID-19 pneumonia, vaccination was significantly associated with lower rates of ICU admission and mortality. These findings suggest that COVID-19 vaccines may provide a potentially important benefit for critically ill patients with COVID-19 pneumonia.

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Abstract #2

“Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events”

Background

Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear.

Methods

In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed.

Results

A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001).

Conclusions

In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide.

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Abstract #3

“Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial”

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is aggressive and difficult to treat. Atezolizumab is a monoclonal antibody that targets the protein PD-L1, which is expressed on some cancer cells and can help them evade the immune system. In this double-blind, phase 2b clinical trial, called ALICE, we evaluated the safety and efficacy of adding atezolizumab to an anthracycline-based chemotherapy regimen in patients with metastatic TNBC. A total of 162 patients were randomized to receive either atezolizumab plus chemotherapy or placebo plus chemotherapy. The primary endpoint was progression-free survival (PFS), which was significantly longer in the atezolizumab group compared to the placebo group (median PFS of 6.3 months vs 3.7 months, respectively; hazard ratio 0.59, 95% confidence interval 0.43-0.81, p=0.0007). Overall survival and objective response rate were also higher in the atezolizumab group, although the differences did not reach statistical significance. Adverse events were similar between the two groups, with the most common being neutropenia, anemia, and nausea. In conclusion, the addition of atezolizumab to anthracycline-based chemotherapy significantly improves PFS in patients with metastatic TNBC, with a manageable safety profile. These findings support the further investigation of atezolizumab in this patient population.

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AI Seinfeld and AI Steamed Hams

Not all may be scary in the world of AI. Several people have taken to using AI to recreate some shows with…interesting results.

One example is AI Seinfeld (ironically titled Nothing, Forever), which appears to have taken from the Seinfeld series in order to produce its own sitcom. Some parts gets decent dialogue, while at other parts of the AI generated show can be rather jarring, as the generated characters can’t seem to sit or move properly with some of them just melting into the scenery at points. This also comes with the fact that an artificial laugh track is randomly introduced at awkward times such as before punchlines, although that may be AI just picking up on how American sitcoms normally go…

In contrast, there have been a few scenes where the characters have actually provided insightful (is that the right word?) commentary, while at other times have even created their own language and spoke to each other in this new language. A bit creepy there.

AI Seinfeld originally streamed on Twitch as a 24/7 livestream with various skits and scenes continuously being generated, until it was taken down for AI Jerry making a comment on trans jokes¹. Supposedly AI Seinfeld returned albeit in a very neutered fashion.

Here’s one collection of scenes for those interested:

But one of my favorite has to be an AI-recreation of the steamed hams meme from The Simpsons, in which Principal Skinner attempts to cover up his poor cooking with Krusty Burgers, ending with his kitchen catching on fire and an Aurora Borealis being blamed for the lights (the meme for those interested).

Someone took to designing an AI which continuously recreates this scene, but apparently drawing from random sources creating an otherwise highly disjointed setup.

Instead of there being an Aurora Borealis, the AI has taken to explaining away the fire as either being:

• The Rapture (“no, that’s just the light from The Rapture”…)

• A dybbuk

• A skinwalker

• A chupacabra

• Werewolves

Among others… The food is also swapped out for random plants, and the schemes for covering up the mishaps have also been just as colorful.

Also, unlike AI Seinfeld AI Steamed Hams has taken to being extremely vulgar at times, dropping F-bombs at random especially with Skinner disparaging himself with crass comments- I think that’s what the young kids call “a mood”.

Here’s some examples. Unfortunately, AI Steamed Hams doesn’t seem as popular as AI Seinfeld so there’s fewer videos.

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There’s spike mRNA in my milk (or maybe not…)

With the recently proposed Missouri House Bill 1169 on labeling products there’s been this increasing concern about mRNA vaccines or such technology getting into the food supply.

Let me be clear; I am not against labeling products and in fact am for greater transparency in labeling. However, when writing my post on Bill 1169 I was curious as to what information was being used to construct the language in the bill, and whether some of the ambiguities may leave room for loopholes in labeling.

That is to say, what actual effect would this bill have on transparency in the future?

In regards to Missouri House Bill 1169

With everything that has happened in the past few years I can understand why there is concern over consumer autonomy and transparency. At the same time, this concern can sometimes be inflated with noise and misinformation, and in some cases this muddying can stem from a lack of science reading and critical thinking.

These fears have now entered into concerns over food supplies and whether things may be introduced without our permission.

Consider the recent discourse over vaccines in food as alluded to in Bill 1169. Edible vaccines have been in development for many years but don’t appear to have gained much traction, whether through feasibility or through regulatory means of approval.

But because of the COVID mRNA vaccines it’s now become the in vogue thing to mention mRNA vaccines, but now being introduced into fruits and vegetables.

This as a model fails from even a foundational biology level, because how exactly would one get mRNA vaccines into lettuce? At the point that such a technology is introduced it’s no longer mRNA because the gene to produce the end-antigen would have to be inserted into the plant, and at that point you’re not really having mRNA vaccines in the same way that the COVID vaccines are designed.

It’d be extremely difficult to introduce pseudouridine in this platform as you’d have to keep feeding such a molecule in the hopes that the plants take them up, and even at that point they may not even use them. The plant may also just end up expressing the antigen anyways (let’s say spike protein, for instance), so why even go through all of this trouble to design the middle-man precursor to the actual immunogenic agent?

Sadie provided me a link in the comments that probably helps explain a lot of the issues in misinterpretations and misinformation.

From UC Riverside

On the surface it would align with all of the concerns that people have been raising. The article even mentions mRNA vaccines in lettuce…

But again, in practice what is actually happening here? As has been outlined, and has been in the works for many years, researchers are inserting the gene into plants i.e. genetically modifying them:

The project’s goals, made possible by a $500,000 grant from the National Science Foundation, are threefold: showing that DNA containing the mRNA vaccines can be successfully delivered into the part of plant cells where it will replicate, demonstrating the plants can produce enough mRNA to rival a traditional shot, and finally, determining the right dosage. 

What’s happening is that the plants are being designed to express the mRNA, whether through transfection with DNA or through genetic modification via insertion of the gene into the plant. The language in the article doesn’t exclude the former, although the feasibility of injecting seeds or plants would appear far too annoying and obnoxious on a large scale rather than just inserting the gene. The bioavailability and degradation of the product is also something that would raise suspicions, as well as dosing issues.

But more important, the process here isn’t describing something novel, and in fact is just describing something that has been around but reinterpreted through a different lens i.e. mRNA.

That is, instead of describing vaccines from the perspective of the antigen that the plants are producing, they’re just taking one step back and describing the mRNA instead.

I’m assuming that the reason articles like the one from UC Riverside described above use the term “mRNA vaccine” is because it’s the “popular” thing right now, even though it appears to be describing a process that is par for the course of biology as a whole.

Also, keep in mind that the research listed above is coming from a hypothetical framework-until their research bears literal spikey fruit then it’s possible that such technologies may not get up off the ground.

I’d like to hear other people’s thoughts on the matter, but for me this doesn’t seem like a damning bit of evidence as has been made out, because from a practicality aspect there’s a lot of issues in application.

Speaking of issues in assessing science, a study from December 2022 has begun to circulate, possibly in part due to tweets such as the one below:

Substack gave a warning that Twitter is blocking Substack from embedding tweets, so I had to print screen the tweet above. The tweet can be found here.

There’s a lot going on here, with one main issue being the fact that the remarks above lack proof of concept i.e. feasibility and practicality.

Note here that the tweet above assumes a direct move of mRNA into milk, appearing to rely on the title and abstract alone.

The study from Zhang, et al.² never models this process. Instead, the study took to isolating exosomes from milk to see if they could serve as a delivery vehicle for mRNA encoding the RBD of the spike protein. This use of naturally-derived products as a delivery vehicle is nothing new- Novavax's COVID vaccine uses saponins to form their ISCOM.

This is a huge difference than just injecting mRNA into cows (which still wouldn’t be good if it comes into practice) since you’d have to provide an explanation for how the mRNA from an injection can become packaged into exosomes in milk.

It doesn’t mean this process may not occur, but that there’s a lot of variability that doesn’t appear to be accounted for, and instead relies on the assumption that this process is actually taking place.

Even stranger, this study never actually provided mice oral vaccines with these milk exosomes, but instead injected these exosomes into the duodenum of mice (emphasis mine):

To further confirm the ability to stimulate neutralizing antibodies, RBD mRNA-milk-exos were injected into the duodenum (i. d.) of 9-11-week-old female BALB/c mice (Fig. 6A). Blood (0.1 mL) was collected on days 0, 7, 14, 21, 28, 35, 42, and 49 for antibody detection before the animals were sacrificed. Using ELISA kits adapted for detecting mouse-derived antibodies, we observed that vaccinated animals produced a relatively constant level of neutralizing antibodies against RBD after the second injection (Fig. 6B, C).

So the researchers weren’t even modeling this supposed oral vaccine development that they continuously describe in their study.

It would appear that two proxies are being used to make this argument:

1. The in vitro study appears to show transfection of mammalian cells with these exosomes is possible.

2. The in vivo mouse study showed an immune response via anti-RBD antibodies.

And it’s these two that are somehow being used to argue that this platform can serve as an oral vaccine, as one may assume that oral administration would lead to quick transfection of cells and an immunological response.

Again, the biggest issue is figuring out the feasibility of this platform. More importantly, given the limitations I find it hard to argue that the study accurately models an oral vaccine (they didn’t even administer the exosomes orally to mice…).

Remember too that the study synthetically packaged the mRNA into milk exosomes, which doesn’t tell us anything about whether this would happen in animals since the exosomes had to be manipulated by researchers. And then, after all of that, how practical would such a process actually be in the long run?

Overall, my biggest concern with the food supply/vaccine discourse is that there’s so much speculation and lack of proof of concepts. Rather than figuring out the feasibility and practicality of these models and studies, it appears that tenuous associations may be inflated to create a narrative that may not actually exist.

It’s worth reiterating that there are viable concerns if companies decide to start using mRNA vaccines for their livestock, or if these sorts of research go further than a conceptual model.

At the same time, the crux of the issue is that when “Idea X” is proposed by “Study Y”, that it then becomes the incentive of readers to scrutinize X and Y to see if they make sense rather than believing X and Y are actually occurring.

This, again, is a problem of Abstract-only reading and why people should engage with studies rather than misinterpreting extrapolations.

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1. Someone in the comments mentioned that the AI was acting up and a different script was used, which apparently led to the characters becoming extremely vulgar in their language and the final result which got them removed from Twitch.

2. An oral vaccine for SARS-CoV-2 RBD mRNA-bovine milk-derived exosomes induces a neutralizing antibody response in vivo

Quan Zhang, Miao Wang, Chunle Han, Zhijun Wen, Xiaozhu Meng, Dongli Qi, Na Wang, Huanqing Du, Jianhong Wang, Lu Lu, Xiaohu Ge

bioRxiv 2022.12.19.517879; doi: https://doi.org/10.1101/2022.12.19.517879