Please keep this going! We need all the non-negative news we can get.
Yesterday I went to a book (actual hardcover books) event* in DC put on by Stripe Press (as many readers will know, they publish books/newsletters/etc on the broad topic of “progress”). I bought a couple of books but I also skimmed one I didn’t buy (yet), Pieces of the Action by Vannevar Bush, a key 20th century figure in technology development and science funding. The preface was written in 1970 and acknowledged that a lot of things looked quite bad, but at the same time a lot of good things were happening (this is a gross oversimplification but you get the gist). Unlike most of the attendees, I was alive in 1970; I was too young then to know what was going on but growing up later, in the rustbelt, things certainly seemed bad, so much so that the progress and prosperity of the 80s and 90s seemed kind of shocking at first.
This is just a long way of saying that it’s corrosive to obsess about how bad things are such that there’s no point in trying to change anything, and that’s the character of so much public discourse. I subscribe to newsletters looking for something different, so I’m happy to see this feature and I hope it continues.
*also there were a *lot* of people there! To talk about books! ❤️
Derek - this is a great concept and I'll look forward to reading on Sundays. A dose of tragic optimism. Love it. RE: GLP-1s, as you continue to explore this topic, I'd be curious to know what percentage of effective medications and interventions are, essentially, accidents. GLP-1s began as diabetes medications. You could argue weight-loss is part and parcel of an effective diabetes therapy. But their potential for things like migraines and addiction (if this stuff holds up) is what I'd call a serendipitous accident. I'm sure there are other examples of these. Similarly, I find it interesting that we still have very little in the way of mechanistic understanding on some of these broader effects. It brings to mind SSRIs, which were initially thought to alleviate depression by increasing the amount of serotonin in the brain (a very specific and bioplausible theory/target). Now, it's pretty well accepted that it's not an increase in serotonin that is working on depression (and anxiety/OCD) but something else. The best guess I've come across is that SSRIs increase overall neuroplasticity, explaining why they tend to work best in conjunction with therapy. (However, after multiple decades, we still know next to nothing about why and how SSRIs work.) But all of this makes me wonder if GLP-1s are having some kind of similar effect on hormonal plasticity or disrupting some other homeostatic groove/rut that gets set in the body and underlies some of these conditions. Who knows. This is all armchair speculation. But I'll be curious to learn more from people who think about and study this all day. As you write, it's fascinating we got here from a giant lizard's saliva.
I can't speak to the number of these accidental treatment discoveries but I can offer another example: I have multiple sclerosis for which I take Dimethyl Fumarate. This chemical started out as an antifungal treatment for soft furnishings. Unfortunately it was found to cause unpleasant skin reactions so that use was discontinued. But not before someone noticed that for some people it had the opposite effect: it seemed to reduce the effects of psoriasis. So it became a treatment. And then, somewhere along the line, someone else noticed that it seemed to reduce relapses or negative effect of MS, so it also became a treatment for that. Which happens to work pretty well for me over the 10 years I have been taking it!
So there we go - fascinating subject! And I think I may have to keep reading.
Derek: Just want to tell you that this is exactly the type of content I love reading and your writing is refreshingly brilliant when I read it. Please keep it up! Thank you 🙏
Absolutely love this. I cover stories of progress / good news across New England and interview people engaged in solving complex problems. The other day I interviewed Congresswoman Maggie Goodlander (NH District 2) and we talked about your book and the new abundance caucus! On a personal level I somehow manage to bring Abundance up in every conversation with friends and family-- my wife and I listened to the audiobook while painting our kitchen.
Hope to amplify and spread all the rational optimism emanating from this stack, keep up the great work!
Regarding the impact of fertility on climate change: I think the conjecture that people are foregoing having children because "they’re afraid their children will contribute to the destruction of the planet" inverts the problem and misses the point. The fear I hear from youth and my grandparent cohort is that the destruction of the planet will harm my children.
I love this concept and appreciate your smart, well-researched and humorous writing on these topics. Going from reading news about asinine potential tax increases on wind and solar to reading your piece, I felt actual physical relief as I shifted from outrage and fear to curiosity and excitement. My heart rate balanced, my muscles relaxed, I smiled, I felt optimistic. Did you anticipate that reading The Sunday Morning Post would have positive health benefits? Thank you and please keep it up!
Excellent column. For the GPL1 bit, consider that perhaps the treatment reduces over carbohydrate, especially simple sugar, consumption and, thus, inflammation at the cellular level. Inflammation generally leads a bunch of negative effects. Reduce inflammation, and many 'chronic' health issues fall in severity, if not away entirely. So GPL1 usage could be more correlation than causation.
This is a great idea for a Sunday post. More positive stories getting eyes/ears the better. Despite the doom & gloom in the news, the march of innovation continues to move swiftly forward.
Re: GLP-1s - the effects of this class of medicine in CNS diseases is really interesting. In addition to the migraine data you shared, there are a swath of other small P1 and P2 studies in other CNS diseases (namely Parkinson's, Alzheimer's, and Substance Abuse). This therapeutic area is a great test case to see how powerful the non-weight loss effects of this class can be. Notably Novo Nordisk has their P3 EVOKE and EVOKE-PLUS studies in Alzheimer's set to read out later this year. This will be the first test to see whether the neuroprotective signals from this class are real.
What's odd about GLP-1s for brain diseases is that, these drugs have very little blood brain barrier penetration. Some studies indicate that these agents can cross the blood–brain barrier and exert neuroprotective effects by reducing oxidative stress, modulating neuroinflammation, and supporting dopaminergic neuron survival. But still the BBB penetration isn't spectacular and varies quite a bit by molecule. The likes of semaglutide and tirzepitide actually have quite poor BBB penetration. So if therapeutic CNS effects are occurring, they are happening indirectly, probably through the gut-brain-axis with these molecules.
More peculiarly though is that many brain regions, even deep brain regions that are harder to penetrate, have GLP-1 receptors. So why? They must have a role, right? And would we get more neuroprotective effects if we specifically design a GLP-1 agonist for BBB penetration into these deeper brain regions? Will those effects be better than what we see with GLP-1s that don't really penetrate the brain all that well? Those are some exciting questions that we will get answers to over the coming few years as new fit-for-purpose versions of this class are developed by drug cos.
I've written about the expansion of GLP-1s on here extensively from a drug developer/biotech professional's point of view, so please feel free to check out my work if helpful to some of the other things you are working on (some links below). DM me if you need access. Happy to comp you.
Nice start but one quibble. Not a good example of pleiotropy. Sickle cell is thought to persist because of its protective effect on malaria and the mechanism of cell deformation is closely related to the protection. Better would be the many different functions of various mediators like TGF-beta.
Finally, someone said it not everything needs to be doom and gloom to be relevant. I love the idea of content that values long-term impact over clickbait chaos.
Slow change is still change and honestly, it’s often the kind that actually shapes our lives
Please keep this going! We need all the non-negative news we can get.
Yesterday I went to a book (actual hardcover books) event* in DC put on by Stripe Press (as many readers will know, they publish books/newsletters/etc on the broad topic of “progress”). I bought a couple of books but I also skimmed one I didn’t buy (yet), Pieces of the Action by Vannevar Bush, a key 20th century figure in technology development and science funding. The preface was written in 1970 and acknowledged that a lot of things looked quite bad, but at the same time a lot of good things were happening (this is a gross oversimplification but you get the gist). Unlike most of the attendees, I was alive in 1970; I was too young then to know what was going on but growing up later, in the rustbelt, things certainly seemed bad, so much so that the progress and prosperity of the 80s and 90s seemed kind of shocking at first.
This is just a long way of saying that it’s corrosive to obsess about how bad things are such that there’s no point in trying to change anything, and that’s the character of so much public discourse. I subscribe to newsletters looking for something different, so I’m happy to see this feature and I hope it continues.
*also there were a *lot* of people there! To talk about books! ❤️
Derek - this is a great concept and I'll look forward to reading on Sundays. A dose of tragic optimism. Love it. RE: GLP-1s, as you continue to explore this topic, I'd be curious to know what percentage of effective medications and interventions are, essentially, accidents. GLP-1s began as diabetes medications. You could argue weight-loss is part and parcel of an effective diabetes therapy. But their potential for things like migraines and addiction (if this stuff holds up) is what I'd call a serendipitous accident. I'm sure there are other examples of these. Similarly, I find it interesting that we still have very little in the way of mechanistic understanding on some of these broader effects. It brings to mind SSRIs, which were initially thought to alleviate depression by increasing the amount of serotonin in the brain (a very specific and bioplausible theory/target). Now, it's pretty well accepted that it's not an increase in serotonin that is working on depression (and anxiety/OCD) but something else. The best guess I've come across is that SSRIs increase overall neuroplasticity, explaining why they tend to work best in conjunction with therapy. (However, after multiple decades, we still know next to nothing about why and how SSRIs work.) But all of this makes me wonder if GLP-1s are having some kind of similar effect on hormonal plasticity or disrupting some other homeostatic groove/rut that gets set in the body and underlies some of these conditions. Who knows. This is all armchair speculation. But I'll be curious to learn more from people who think about and study this all day. As you write, it's fascinating we got here from a giant lizard's saliva.
I can't speak to the number of these accidental treatment discoveries but I can offer another example: I have multiple sclerosis for which I take Dimethyl Fumarate. This chemical started out as an antifungal treatment for soft furnishings. Unfortunately it was found to cause unpleasant skin reactions so that use was discontinued. But not before someone noticed that for some people it had the opposite effect: it seemed to reduce the effects of psoriasis. So it became a treatment. And then, somewhere along the line, someone else noticed that it seemed to reduce relapses or negative effect of MS, so it also became a treatment for that. Which happens to work pretty well for me over the 10 years I have been taking it!
So there we go - fascinating subject! And I think I may have to keep reading.
Love this feature. More please!
Derek: Just want to tell you that this is exactly the type of content I love reading and your writing is refreshingly brilliant when I read it. Please keep it up! Thank you 🙏
Excellent: already looking forward to the next post.
Brilliant idea for a feature
Absolutely love this. I cover stories of progress / good news across New England and interview people engaged in solving complex problems. The other day I interviewed Congresswoman Maggie Goodlander (NH District 2) and we talked about your book and the new abundance caucus! On a personal level I somehow manage to bring Abundance up in every conversation with friends and family-- my wife and I listened to the audiobook while painting our kitchen.
Hope to amplify and spread all the rational optimism emanating from this stack, keep up the great work!
Regarding the impact of fertility on climate change: I think the conjecture that people are foregoing having children because "they’re afraid their children will contribute to the destruction of the planet" inverts the problem and misses the point. The fear I hear from youth and my grandparent cohort is that the destruction of the planet will harm my children.
Oh and that footnote is everything.
I love this concept and appreciate your smart, well-researched and humorous writing on these topics. Going from reading news about asinine potential tax increases on wind and solar to reading your piece, I felt actual physical relief as I shifted from outrage and fear to curiosity and excitement. My heart rate balanced, my muscles relaxed, I smiled, I felt optimistic. Did you anticipate that reading The Sunday Morning Post would have positive health benefits? Thank you and please keep it up!
Excellent column. For the GPL1 bit, consider that perhaps the treatment reduces over carbohydrate, especially simple sugar, consumption and, thus, inflammation at the cellular level. Inflammation generally leads a bunch of negative effects. Reduce inflammation, and many 'chronic' health issues fall in severity, if not away entirely. So GPL1 usage could be more correlation than causation.
Interesting topics. I'll take a look but I'm more the self development, personal improvement, stop overthinking guy.
This is a great idea for a Sunday post. More positive stories getting eyes/ears the better. Despite the doom & gloom in the news, the march of innovation continues to move swiftly forward.
Re: GLP-1s - the effects of this class of medicine in CNS diseases is really interesting. In addition to the migraine data you shared, there are a swath of other small P1 and P2 studies in other CNS diseases (namely Parkinson's, Alzheimer's, and Substance Abuse). This therapeutic area is a great test case to see how powerful the non-weight loss effects of this class can be. Notably Novo Nordisk has their P3 EVOKE and EVOKE-PLUS studies in Alzheimer's set to read out later this year. This will be the first test to see whether the neuroprotective signals from this class are real.
What's odd about GLP-1s for brain diseases is that, these drugs have very little blood brain barrier penetration. Some studies indicate that these agents can cross the blood–brain barrier and exert neuroprotective effects by reducing oxidative stress, modulating neuroinflammation, and supporting dopaminergic neuron survival. But still the BBB penetration isn't spectacular and varies quite a bit by molecule. The likes of semaglutide and tirzepitide actually have quite poor BBB penetration. So if therapeutic CNS effects are occurring, they are happening indirectly, probably through the gut-brain-axis with these molecules.
More peculiarly though is that many brain regions, even deep brain regions that are harder to penetrate, have GLP-1 receptors. So why? They must have a role, right? And would we get more neuroprotective effects if we specifically design a GLP-1 agonist for BBB penetration into these deeper brain regions? Will those effects be better than what we see with GLP-1s that don't really penetrate the brain all that well? Those are some exciting questions that we will get answers to over the coming few years as new fit-for-purpose versions of this class are developed by drug cos.
I've written about the expansion of GLP-1s on here extensively from a drug developer/biotech professional's point of view, so please feel free to check out my work if helpful to some of the other things you are working on (some links below). DM me if you need access. Happy to comp you.
Podcast on GLP-1s for the brain: https://www.bigpharmasharma.com/p/drug-dealin-ep4-ozempic-for-the-brain?utm_source=publication-search
Post on GLP-1 data in CNS diseases: https://www.bigpharmasharma.com/p/what-2025-holds-for-glp-1s-in-brain?utm_source=publication-search
Clinical Trial Landscape of non-T2D non-Obesity GLP-1 studies: https://www.bigpharmasharma.com/p/two-charts-that-highlight-the-future?utm_source=publication-search
Post more like this every week
Nice start but one quibble. Not a good example of pleiotropy. Sickle cell is thought to persist because of its protective effect on malaria and the mechanism of cell deformation is closely related to the protection. Better would be the many different functions of various mediators like TGF-beta.
Finally, someone said it not everything needs to be doom and gloom to be relevant. I love the idea of content that values long-term impact over clickbait chaos.
Slow change is still change and honestly, it’s often the kind that actually shapes our lives