I did not enjoy getting my recombinant shingles vaccine (Shingrx). I rarely have strong reaction to vaccinations, but the adjuvant in this one really did give me a sore arm, and the second shot (as one might expect) brought on that symptom even more strongly. But I am very happy indeed that I got that series of shots, because the evidence has continued to pile up that this vaccination is associated with a significantly lower risk of dementia later in life. These studies involve large cohorts of patients from several locations around the world, and they all point in that same direction. It very much looks like this is a real effect; I’m unaware of any similar effort to look for it where this signal was not observed.

So if we stipulate that, the next question is How Come That Happens? It’s quite possible that persistent herpes zoster virus imposes some sort of immune/inflammatory burden that contributes to neurodegeneration over time, but that idea needs more data to back it up. There may be other cross-contributions of the immune response to the vaccination at work as well, but we don’t have much to point at there yet, either.

But this new paper makes finding such links a matter of even greater importance. The authors show that this same vaccine is associated with a 9% decrease in cardiovascular disease endpoints over the next seven years. Specifically, disease burden was lower for ischemic heart disease, for heart failure, and for atrial fibrillation, and in male patients it showed a lower burder for ischemic stroke. This study involved over 36,000 patients who received the recombinant vaccine in 2018 and a similar 36,000 who received the older live-attenuated vaccine in 2017. That’s a pretty solid natural-experiment control. The comparison between the two types of shingles vaccine is even more impressive when you consider that the earlier vaccine itself had been linked in similar analyses to cardioprotective effects all its own. 

This latest work also looked through these two sets of patients for people who got a TDaP vaccine in 2018 versus 2017 and found no cardiovascular effects at all. So it’s not just “any vaccination”, but it has to be said that both influenza vaccination and pneumococcal vaccination have also been linked to cardioprotective effects. And why stop there? I just wrote back in June about lower cardiovascular events in a study of one million veterans who received the coronavirus vaccine. Not all of these appear (so far) to be necessarily driven by just prevention of myocarditis (direct infection of cardiac tissue), so that simple explanation doesn’t seem to be enough. There are various hypotheses about antibody effects on various types of oxidized LDL particles or on the inflammatory cascades that are found in atherosclerosis, but these too need to be shored up.

Taken together, though, all of this work strongly suggests that more people - especially more older people! - need to get the current vaccines against infectious diseases. They are not only good at preventing the diseases they are targeted for, but they show health benefits above and beyond what you would have anticipated. As for me, as mentioned I have had the recombinant shingles vaccine, and I have had the pneunococcal shot as well. I have had coronavirus vaccines every year since they became available, and I look forward to getting the latest one soon. I will also cheerfully be getting this year’s influenza shot. I have no desire to get any of those diseases, and since I also have strong desires to avoid cardiovascular events and dementia I am just thrilled that it appears that I'm doing something about those at the same time.

Anti-vaccine activists are wrong about the benefits of these shots, and the ones who are currently in high positions in our public health system are worse than wrong: they are culpable. Downplaying the need for these vaccines has caused and is causing significant mortality and morbidity just by the targeted infectious agents themselves, and that alone seems to me to be a total abdication of responsibility. But more and more it appears that discouraging these shots is also exposing people to higher rates of heart attacks and dementia as they age, and what the hell do we have public health officials for if it is not to help lower the rates of all these things? Well?

We had a weird story develop over the weekend here in the Cambridge area (and among organic chemists in general). I’m glad that I wasn’t trying to blog it as it happened, because it’s taken some turns!

This all started last Wednesday night, but most of us only heard something on Thursday when word came of an MIT chemistry building that was being closed off because of a report of someone who had been exposed to hazardous material. It became clear that said material was possibly dimethylmercury, which a graduate student had claimed to have synthesized, and who subsequently reported themselves to a local emergency room. And you can see why that caused a stir (but read on!)

Dimethylmercury is very, very bad news. It is obviously something I will not work with, but it’s never been the subject of a blog post here in that category because unfortunately there’s nothing lighthearted about the subject. Not after the death of Karen Wetterhahn in 1997. That story should be well known to chemists everywhere, but the short version is that Prof. Wetterhahn (at Dartmouth) was accidentally exposed in August of 1996 to a few drops of liquid dimethylmercury on her latex-gloved hand. What she didn’t know (and what none of us really knew) was that this compound rapidly penetrates such gloves, which meant that Wetterhahn was exposed to skin contact within seconds. Toxicologically, it is probably the worst of the organomercurys, which are of course a dangerously toxic group of compounds overall. Her precautions for handling the compound were the standard at the time, it should be noted.

Prof. Wetterhahn began to notice general symptoms within weeks. Early in 1997 she began to show neurological problems, and within weeks she had collapsed into a vegetative state. She was removed from life support in June. She had very high levels of mercury in her blood, and all attempts at chelation therapy to remove it were ineffective. That’s surely because it had spread throughout her body by the time the problem was recognized, but frankly no one can be sure if there were any measures that could have been effective enough after the initial exposure. This horrifying incident led to a complete re-evaluation of the use of dimethylmercury in synthetic and analytical chemistry, where among other things it had been the reference peak standard in mercury NMR experiments.

No one should be synthesizing this compound and no one should be working with it at all. I cannot think of any scientific result it might offer that is worth the risk or where no alternative route can be found. So you can see why the MIT incident made everyone jump! But subsequent updates have made the situation rather more complicated. On Saturday, the university said that “emerging information called into question whether this compound was in fact synthesized”, and also that the student’s blood work had shown no signs of mercury exposure. Which is good to hear. The university has re-opened the lab building as of today.

What we don’t know is what this student was up to: why they seem to have thought that they needed to synthesize dimethylmercury and what chemistry they actually performed. I don’t know when we’ll find out more details - if we ever do - but the fact that the building and lab are open again today makes a person think that there wasn’t any actual attempt at all. You can’t make dimethylmercury without going through some other pretty damned toxic species and generating a very serious waste stream, and I find it hard to believe that this could be cleaned up so thoroughly, so quickly. Mercury is of course easily detected to very low levels with decent analytical chemistry equipment, which MIT has plenty of. So my conclusion is that the main problem here is likely not a synthetic chemistry one, but I will be very glad to hear more details.

In case it’s needed, though, a word to anyone who is still intrigued by this compound: synthesizing or working with dimethylmercury at this point is not cool, edgy, transgressive, or something to impress the crowd with. It is a wildly stupid idea that will endanger your life and the lives of anyone unlucky enough to be around you while this work is going on. Not to mention anyone who is simply unlucky enough to be downwind. It’s like working with homemade nerve gas, but at least that kills you quickly. With compounds like this, everyone knows the dangers, and honestly - I’m going to be offensive here - it’s hard not to think that anyone who goes ahead after knowing them deserves what they get. But the people who will have to clean up after you don't. I’m glad that this MIT student is OK, because I’m glad in general when someone is saved from a horrible, inexorable death. But come on.

First off, a note that posting will be a bit irregular this week, but I wanted to let people know that I'm definitely still around! So here's something to talk about:

There's a good new paper in JAMA Internal Medicine looking at a large recent data set in Covid-19 vaccinations in an older population. It's from the Veterans Administration, looking at about one million veterans who got a flu vaccine in 2024, and over three hundred thousand of them also got a coronavirus vaccine. Following up on these cohorts, the authors find that there was a 38% reduction in coronovirus-related major cardiovascular events in that latter vaccinated category, which is very nice to see. Even more interesting is that there was a 24% decrease in all-causes cardiovascular events (that is, including patients who were never diagnosed with a coronavirus infection during this period. That's quite impressive - comparable to the benefits of statins in at-risk patients (and it should be noted at the same time that the effects of statin therapy in otherwise healthy older patients do not seem to be particularly meaningful, although debate continues on that question).

As this excellent overview at Stat details, the most likely explanation for these numbers is a significant undercount of how many of these patients were actually infected with the coronavirus. But that's worth thinking about, too, because that leads one to the idea that many of them may have not felt all that sick (and never bothered getting tested for the virus as a result) but still had enough of an infection to raise their risk of cardiovascular trouble. And that makes a case for really getting those vaccination numbers up higher - the estimate from the paper's authors is the possible avoidance of 3,500 major cardiovascular events per million patients vaccinated in this population.

As the Stat article correctly says, this might surprise some people who associated the coronavirus vaccines (particularly the mRNA ones) with the side effect of myocarditis (particularly in young men). And that's a real finding - the vaccine did produce this in a small number of patients. But (and I've said this before), you know what gives people mycarditis at a significantly greater rate and in greater severity when it does occur, and not just in young men? Yeah: getting infected with the coronavirus. So it's still a very good tradeoff, and in this older population it's almost certainly an even better deal.

This will not sit well with the people who believe that the mRNA coronavirus shots have ravaged the world's population and are the cause of a whole list of diseases (cardiovascular death being a prominent one, for sure). You don't have to go far to find these folks - heck, some of them will be showing up in the comments to this post once they become aware of it, although I (as has been the policy here since the worst days of the pandemic) will not even let the most scurrilous of these even publish to the comments section in the first place. The signal/noise of the world is not improved by several paragraphs of poorly punctuated ranting about secret depopulation experiments, 5G nanobots, irreversible changes that make vaccine recipients subhuman and thus put the few, the brave, who haven't been vaccinated in the position of the Last Pure Humans on Planet Earth, and on and on. Nope, there's plenty of that crap out there already and I see no need to give it a platform here.

But the irony is rather thick: coronavirus vaccines not only keep people out of the hospital with severe viral infections - a fact that has been irrefutably proven in many large studies - but also help to keep elderly patients from dying of major cardiac events. Add that to the mounting evidence that the shingles vaccine helps to prevent dementia in these same age groups, and the recommendation has to be that older patients should be getting vaccinated far more often than they do. I'm not quite 65 yet, but I have taken all of these shots and will continue to get the updated coronavirus ones as they become available. Because I really think that it would be irresponsible to do otherwise.

There are a couple of very interesting AI-assisted-chemistry paper out this week, and I have been trying to find the time to take them on. Let’s do this one first. It’s a report on “Co-Scientist”, a system to help propose hypotheses, potential mechanisms, et al. for biomedical discovery.

The authors first applied this in what I think is a good test bed for it: drug repurposing. Let’s put aside the not-all-that-high success rates seen in these efforts, because nothing in this field has a high success rate when you get right down to it. I saw that it’s a good area because existing drugs at least have a lot of fairly reliable data around them, and that’s what a system like this needs most of all.

The first test was looking for new single-agent and combination therapies in oncology. The program suite is well-named, actually, because it turns out that human input and judgement is required all along the way (you may be relieved to hear). The beginning step was prediction of the effects of 2300 approved drugs profiled across 34 cancer types, with the predictions then human-evaluated by one or more oncologists. The most actionable predictions were deemed by this review to be the ones for acute myeloid leukemia (AML). The human team selected four different AML cell lines and one control line to evaluate compounds in, but as the paper correctly notes, this is more of a reality check than any kind of big step into clinical developability.

The selection of compounds to assay (like the selection of the particular cancer type and the selection of cell lines to evaluate it) was made with “meticulous expert oversight”, i.e. human oncologists. Thirty drug candidate proposals were reviewed by this committee for their potential AML relevance, and five were selected: binimetinib (an MEK/MAP2K inhibitor), pacritinib (which inhibits JAK2 among other kinases), cerivastatin (an HMG-CoA reductase inhibitor statin drug whose withdrawal from the market ultimately led to the closure of the entire research site I used to work at!), pravastatin (another drug in that same class), and dimethyl fumarate. The first three showed activity in relevant cell assays, with binimetinib being the clear winner in potency.

But hold on: I would have to add at this point that targeting the MEK pathway in AML (as with binimetinib) is not exactly a new idea, with a number of lines of research having been investigated. As for the other two that showed cell activity, pacritinib has already been into the clinic in some AML subtypes, and the unusually strong ability of cerivastatin to induce apoptosis in AML cell lines was noted in the literature 25 years ago (which work could also have predicted pravastatin’s lack of activity here. I do not see citations of any of those references in the manuscript in its current form.

The team then used the Co-Scientist system without oversight to propose single-agent drug repurposing ideas for AML, but as before, they did have an expert human panel review its proposals. The paper doesn’t say how many candidates went into that step, but three came out the other end of the review: nanvuranlat (a LAT1 inhibitor), KIRA6, and leflunomide. When these went into the cell assays, only KIRA6 showed activity. It’s an IRE1-alpha inhibitor, and as the paper does note, that mechanism has actually been proposed before as an AML therapy (although not with this particular compound). I’m not sure if I would call that “repurposing” or not, but that’ll vary on your own definition.

Of course, oncology is all about drug combinations, cancer cells being what they are. The paper goes on to look for possible synergistic combinations, and I would have to say up front that synergy in these situations is a lot less common than you’d hope for. The results were complicated, not that that came as a surprise, I’m sure. In one cell line (MOLM-13) a number of the combinations did show at least additive activity, but in another (KG-1a), there was a wide range of results, with some combinations apparently cancelling each other out. As the authors put it, “Further mechanistic studies will be required to define the molecular determinants of response to combination therapy across AML subtypes, and to identify predictive biomarkers that could enable rational regimen selection”, and they sure are right about that.

The other aspects of the paper are rather less well-documented in this manuscript, but that’s because they are covered in other publications. There’s a paragraph or so about using Co-Scientist with human hepatic organoids and cell imaging to come up with new repurposing ideas for liver fibrosis. The one that they specifically mention is vorinostat (there’s more on that here in a separate paper), but as before, a look through the literature shows that this compound as well has activity against fibroblasts and in other models of fibrosis in general. Indeed, the entire class of HDAC inhibitors (of which vorinostat is the prototype) has been investigated in fibrotic disease models and in liver fibrosis in particular, up to animal models. I think it’s good that the system picked up on this, but this is not exactly a de novo result. I should note that none of the papers just mentioned appear to be referenced in the current manuscript, nor do I find references to them in the separate manuscript on this work linked above.

There’s also a mention of Co-Scientist recapitulating a very recent result on an antibiotic resistance mechanism, the exchange of capsid-forming phage-inducible chromosomal islands (cf-PICIs) to spread resistance genes. The system appears to have proposed the same mechanism that the research team had arrived at, which is that these interact with specific phage “tails” to move into new hosts. You can find more on that in this paper and in this one. And that does seem quite useful, using the system as a focused “results digester”. It would be interesting to see what its proposals would have been along the way as the experimental data developed - I suppose this could be recapitulated, with some effort - and if the experiments themselves would have been redesigned and perhaps converged on the answer more quickly. Or not! It would be quite useful to know.

My overall take is that this looks like a promising system, especially for uses like that last one, where you have a large corpus of experimental data and would like to see what the software makes of it. I’d like to see some other examples of just that sort of test being run (where you know the answer and want to see if Co-Scientist arrives at it and at what stage). The open-literature drug repurposing work is to me more of a mixed bag. I think it’s good that the system identified the mechanisms that it did, but I don’t think that the paper does enough to point out that none of these ideas are without precedent - in some cases, a lot of precedent. I wonder how much of the human-review steps mentioned involved people noticing such papers and prioritizing those compounds and mechanisms (naturally enough!) But as you might imagine, the publicity around this work seems to be pointing in the other direction entirely, which I don’t think is doing anyone much of a service. We definitely need all the help with the literature that we can get, but hype we have enough of already.

I’m working on a big post or two, but I did want to get something up today. Have a look at this rather disturbing news from the mouse model world, published here at Science. The authors went to the trouble of genotyping 611 mice tissue samples representing 341 strains at the MMRRC (Mutant Mouse Resource and Research Centers), and as the paper notes, rather dryly and through pursed lips, “Users’ expectations for congenic strains based on nomenclature are not consistently met”.

Yeah, you could say that: nearly half the mice were not really what they were labeled as, with failures at several levels. Worries about this have been building for years as sequencing technology became more and more capable, but I think that this is by far the largest-scale and most detailed look at the problem. To be sure, many of the inconsistencies are believed to be relative minor, but not all of them, for sure. Some of the problem is in the naming conventions used, which are probably promising more than they can deliver:

In addition to the inconsistencies between reported names and genotypes reviewed above, mouse nomenclature as defined by the ICSGNM (10) is not designed to reflect the complexities and nuances in the genetic makeup of many strains. However, names matter, and most users of mouse models have definite expectations for congenic strains based on our frequent conversations with MMRRC and MiniMUGA customers, and with scientists at professional conferences. For example, users expect that congenic names denote strains with the only contribution of the donor strain occurring in the chromosome carrying the relevant mutation. They also expect that such strains are inbred and thus have extremely high levels of genome replicability. These expectations are not consistently met in the MMRRC sample set referenced above, as naming rules allow for a wide range of variation of congenicity and inbreeding levels . . .

A great many might be best described as “incipiently congenic” at best, and the proposal is to capture this in thesummary description of each strain rather than trying to work it into the names themselves. The authors detail an “MMRRC Strain GQC Report” format that tries to get across the key messages using the same layout and the same terms across all the samples - type of strain, the allele and locus of interest, the primary and secondary genetic background, and whether or not the genome is truly replicable (and why not, if that’s the case). It’s designed as well to be able to flag the all-too-common situation of some genetic contributions from yet a third strain of mice along the way., and it also has warnings for constructs that include things that could mess up a variety of experiments, such as having cre recombinase in there or genes for various fluorescent proteins.

It looks like well over a hundred strains have had such reports generated, and teams are working their way through the rest. One hopes that this standard will catch on with other such mutant animal repositories, because there’s no reason whatsoever to think that they have been immune from the problems that got us to this situation. If we’re going to do animal research - and we still have to - we should absolutely be getting the most value out of it and wasting the least number of animals (and the least time and money, needless to say). This is both a scientific and an ethical charge, and I’m glad to see it being addressed.

The arXiv preprint server has become essential to several scientific fields, and has inspired similar services like BioRxiv and ChemRxiv. But the generative AI age has been hard on these sites, and you can see it by their steady imposition of new rules.

Last November, arXiv announced that it was clamping down on the submission of review articles, particularly in computer science. These were becoming alarmingly easy to put together (often as not padded out with references that didn’t even quite exist), and the moderators were getting overwhelmed. No new reviews would be accepted in computer science, they ruled, unless they had already been through a peer-review process at a journal (or for a conference), which sort of turned the entire idea of the arXiv on its head in that manuscript category. But you can understand why.

Then in late January came the announcement that first-time submitters would need an endorsement from another author who had published there before. The stated reason was a rise in outright fraudulent submissions. That article says that the moderator's rejection rates had tripled over 2025 and were apparently still rising, and something obviously had to be done.

Now the chair of the site’s computer science editorial committee (Thomas Diettrich) has turned the flames up. “If the submission contains incontrovertible evidence that the authors did not check the results of LLM generation, it means we can’t trust anything in the paper. The penalty is a 1-year ban from arXiv followed by the requirement that subsequent arXiv submissions must first be accepted at a reputable peer-reviewed venue”. He went on to give examples of such evidence, including the above-mentioned hallucinated references (to papers that just don’t exist) or the presence of meta-comments from the LLM software ("Here is your summary" and so on).

Those fake references are indeed becoming a plague, as illustrated by this manuscript at arXiv itself. Those authors set a lower bound of over 146,000 hallucinated citations appearing in 2025, and it's been rising sharply. This obviously threatens the integrity of the scientific literature itself, and that really didn’t need to take any more torpedos, thanks. If we don’t do something about this we run the risk of an eventual painful de-slopping process, and it would be a *lot* better for everyone if we blocked that crap from getting into the literature in the first place. It’ll be a race. . .