Cell is a recurring publication in the Astral Codex Ten archive, appearing 4 times across 4 issues between May 20, 2022 and August 14, 2025. The archive places it in contexts such as "Leaving aside Cell , a more specialized biology journal"; "Then there are more recent publications that are prestigious: Cell, for instance, was founded in 1974"; "such as the rise of another prestigious journal: Cell". It most often appears alongside Nature, Science, aducanumab.
- Article page
- Cell
- Mention count
- 4
- Issue count
- 4
- First seen
- May 20, 2022
- Last seen
- August 14, 2025
Outbound links
- http://onlinelibrary.wiley.com/doi/10.1113/EP085647/full
- https://apnews.com/article/trump-medicare-coverage-wegovy-zepbound-54bf291135fa9efec7d0ad9672c850a1
- https://archive.org/details/cellularbasisofb0000kand
- https://astralcodexten.substack.com/p/book-review-san-fransicko/comment/7319018
- https://astralcodexten.substack.com/p/know-your-amphetamines#comment-1120873
- https://az620379.vo.msecnd.net/static/files/docs/09db8efd-1031-404a-bd0d-e431236f3313.pdf
- https://doi.org/10.1016/j.cell.2019.05.056
- https://doi.org/10.1016/j.cell.2019.09.001
- https://doi.org/10.1016/j.mehy.2019.109468
- https://doi.org/10.1177/10738584221086488
- https://dynomight.net/
- https://elifesciences.org/articles/61907
Issue trail
Related pages
Source context
The world of scientific publishing is organized as a hierarchy of status, much like the hierarchy of angels in the Abrahamic religions. At the bottom are the non-peer-reviewed blog posts and Twitter threads. Slightly above are the preprint servers like arXiv, and then big peer-reviewed journals like PLOS One. Above those are all the field-specific journals, some with higher reputation than others. And at the top, near the divine presence, are the CNS journals: Cell, Nature, and Science.
For an actual hierarchy of journals based on citation data, see this paper, which puts Nature and Science at the top. Might be worth mentioning that it comes from a journal in the Nature Publishing Group family. Leaving aside Cell, a more specialized biology journal that seems to have gotten into the CNS acronym the same way Netflix got into the FAANG acronym, Nature and Science are very similar. They both publish articles in all scientific fields. They both date from the 19th century. They’re published weekly. They jointly won a fancy prize for services to humanity in 2007. And having your paper in either is one of the best things that can happen to a scientist’s career, thanks to their immense prestige. But how, exactly, did Nature and Science become so prestigious? This is the question I hoped Making Nature: The History of a Scientific Journal, a 2015 book by historian of science Melinda Baldwin, might answer. It focuses on Nature, but much of its lessons can likely be extrapolated to Science considering their similarity. I grew curious about this when I realized that most researchers treat journal prestige as a given. Everyone knows that Nature and Science matter enormously, yet few would be able to say why exactly. But this is important! Prestigious institutions, from universities to media companies to major sports competitions, have a huge impact on the world. It’s useful to understand how they came to be, beyond “being famous for being famous.” One reason this is more difficult than it sounds is that we often settle for superficial answers. Selectivity, for instance, is a common explanation: prestige simply comes from obtaining what is hard to obtain, such as a Harvard degree, an Olympic medal or a Nobel Prize. Nature is indeed highly selective, accepting less than 10% of submitted articles (and the vast majority of papers are not even deemed worthy of a submission to Nature by their authors). Yet harsh selectivity alone cannot explain prestige, or it would be trivial to launch a prestigious journal or university just by setting an artificially low acceptance rate. Another facile explanation is longevity. It’s true that prestigious institutions are often old, and indeed Nature has been around for more than 150 years since its birth in 1869. Science is only slightly younger, having been founded in 1880. But there are many older scientific journals: the oldest one, the Philosophical Transactions of the Royal Society, was created two hundred years before Nature, in 1665. Then there are more recent publications that are prestigious: Cell, for instance, was founded in 1974. The correlation between prestige and longevity is real, but imperfect. It also says nothing of causation: does longevity cause prestige, or does prestige cause longevity? What matters is not the span of time per se, but the specific events that happened — in other words, the history. Making Nature, while not specifically about prestige, gives us exactly that. We’ll first examine the origins of Nature and how it disrupted the publishing landscape of its time (Part I). Then we’ll study the factors that allowed it to build a reputation during its first century of existence (Part II). We’ll end with a focus on the 1970s, when selectivity and prestige suddenly became important to Nature and scientific publishing in general (Part III). I. On the Origins of Nature The story begins with Nature’s founder and first editor, Norman Lockyer. Lockyer had a cushy job as a civil servant in the British government, but dabbled in astronomy in his spare time. In the 19th century, dabbling in astronomy in your spare time could be an intellectually productive hobby: the line between professional and amateur science was blurrier then, and it wasn’t hard to contribute original research even without formal training. During the 1860s, Lockyer published several papers on astronomical observations, the most consequential of which might be the co-discovery and naming of the element helium, from his studies of the sun. His reputation grew among the “men of science” (as scientists called themselves then) of Victorian Britain, and he was soon elected to the Royal Society. But astronomy was an expense, not a source of income. Lockyer routinely supplemented his government job by writing nonspecialist scientific articles and books for a lay audience. Then, one day, he had an idea for a new kind of publication. It would be a weekly periodical to disseminate scientific knowledge to the broader public — but unlike the other periodicals that existed at the time, it would be written by the prominent men of science themselves. It would have a simple, evocative name: Nature. Lockyer summarized the two aims of Nature like this: FIRST, to place before the general public the grand results of Scientific Work and Scientific Discovery, and to urge the claims of Science to a more general recognition in Education and in Daily Life; And, SECONDLY, to aid Scientific men themselves, by giving early information of all advances made in any branch of Natural knowledge throughout the world, and by affording them an opportunity of discussing the various Scientific questions which arise from time to time. In other words (and getting rid of the old-fashioned capitalization of random adjectives and nouns), Nature was meant to do two things: communication from scientists to the public, and communication among scientists. It was an interesting idea. It was also a new one; until then the two aims had been separate. Recall that scientific journals have existed since 1665. During their first two hundred years, they primarily served to record the meetings of learned societies. The Philosophical Transactions of the Royal Society were originally just that: summaries of whatever “philosophical” questions were discussed at the Royal Society. Aside from journals, specialized books were common and were in fact the higher-status way to communicate science in Victorian Britain. Charles Darwin’s On the Origins of Species, published in 1859, is the most famous example. Informal correspondence between scientists was also a major, but private, channel: Darwin wrote more than 15,000 letters in his lifetime, enough to fill 30 volumes. With the exception of some books, none of the above were intended for laypeople. Educated non-scientists (professionals, clergymen, statesmen, etc.) instead got their science news from generalist or literary periodicals such as the Athenaeum magazine. The articles in those publications were not written by specialists, but by journalists and dilettantes. Lockyer’s view, shared with his close supporter Thomas Huxley — a biologist known for defending Darwinian evolution — was that they were riddled with errors and theological overtones. It would be better, they thought, if scientists did the work of communicating their research themselves. It was bold of Lockyer and Huxley to assume that scientists would be interested in doing this communication work. They weren’t. Almost immediately after Nature was founded, its contributors ignored the popularization part (“not a high-status undertaking,” Baldwin’s book says) and focused on the intra-science communication part. They did write summaries and abstracts of their own research, as Lockyer had intended, but they expected that their readers would be other men of science. Within three years, the educated laypeople who were Lockyer’s target audience were complaining that they could no longer understand the contents. Thus the first of Nature’s two aims was met mostly with failure. Fortunately, this was balanced out by unexpected success at the second aim. Scientists did actually enjoy writing for Lockyer’s magazine, in large part because it was published weekly. They found that writing a summary of their own research in Nature was an excellent way to share their results quickly and gain attention from other scientists. Books were slow; Darwin took many years to write and publish On the Origin of Species, for instance. The journals of scientific societies were slow; you had to wait for a meeting to take place and then for the meeting’s “transactions” to be published. Private correspondence was fast, but it wasn’t public. Through publication speed, as well as other factors as we’ll see below, Nature filled a niche in the ecosystem. It was the Twitter of 19th-century British science. Soon enough, this model would be copied, most notably by the journal Science in 1880. According to its first editor, Science was explicitly meant to, “in the United States, take the position which ‘Nature’ so ably occupies in England.” In just a few years, Nature had disrupted scientific publishing and established itself as a useful and unique institution of science, recognized by specialists both in the UK and abroad. First page of the first edition of Nature, 4 November 1869 II. One Hundred Years of Building a Reputation Despite its popularity, Nature didn’t become prestigious overnight. Far from it, in fact. Making Nature often reminds us that the journal spent most of its history as a low-grade publication where anything could be printed quickly, as long as it was factually correct. (This was ensured by basic checks from the editorial team; Nature articles were not consistently peer-reviewed until the 1970s.) As late as the 1960s, a researcher publishing a preliminary report in Nature was expected to follow up with a longer paper “in a more serious journal.” In other words, Nature delivered quick and cheap distribution, not luxury brand approval. This changed about fifty years ago, as we’ll see in Part III. But to understand what happened then, we first need to examine the characteristics of the journal in the roughly 100-year period from its early days until prestige took over, starting with a deeper look into publication speed. Publication Speed John Maddox, editor of Nature in the late 20th century, said that “one of Nature’s greatest early assets was the speed of the Royal Mail.” You could write to Nature, be published within a week, and read the replies to your communication within two weeks. This was state-of-the-art communication tech! Consider how many times publication speed is mentioned throughout the first half of the book (emphasis mine): What made Nature unique was, in large part, its ability to act as a venue for . . . discussions via its correspondence columns and its weekly publication schedule. (p. 8) Many British men of science found that one of the fastest ways to bring a scientific issue or idea to their fellow researchers’ attention was to send a communication to Nature. (p. 39) Unlike the literary periodicals, there was almost no delay between the submission of a piece and its appearance in the journal. (p. 63) A second reason Nature’s speed of publication would have been compelling to men of science is that getting one’s work into print quickly had become an increasingly essential part of establishing priority for a scientific finding or theory. (p. 65) Scientific weeklies [such as Nature] played a unique role in researchers’ publishing strategies at the end of the nineteenth century by offering researchers a forum where short articles could be printed quickly. (p. 105) Both the Proceedings [of the Royal Society of London] and the Philosophical Magazine had significant lag times between submission and publication . . ., which made Nature and its weekly turnaround uniquely valuable for the priority-conscious Rutherford. (p. 109) [Rutherford] sent his most interesting experimental results [to Nature] immediately, both as a way of keeping his colleagues updated on his work and as insurance against being scooped as he had in 1899. (p. 112) These quotes highlight two distinct reasons why speed was important. The first, as I hinted at earlier, was Nature’s role as the аcademic social media of its time. It was simply the best way to have discussions about scientific topics — or science itself — that could, unlike private correspondence, reach a large audience. More on this in the next section. The second reason, as shown by the mentions of physicist Ernest Rutherford, was establishing priority. Today we take for granted that being the first to publish new ideas or results is important, but in the 19th century this was less clear. To bring up Darwin as an example again, he kept his thoughts on evolution private for many years, because he wanted to make sure his argument was sound before he submitted it to the public (although he did eventually sense the urgency of publishing the theory before Alfred Russel Wallace did). But as science became professionalized, “not being scooped” became more and more crucial, and the weekly Nature was a good tool to avoid that. All this talk of speed may surprise anyone who has recently submitted a paper to Nature. In 2016, an analysis revealed that the median time for Nature to review a paper was 150 days, i.e. 5 months, up from 85 days a decade earlier. Nature itself reports, for the year 2020, a median time of 226 days between submission and acceptance. We’re a long way from “less than a week.” Why was there a decrease in publication speed? As we might expect, the reason was Nature’s growing popularity, especially among the international scientific community. At least, that’s what happened the first time there was a slowdown, in the mid-20th century. Early on, Nature was a journal for and by British scientists. But in the first half of the 20th century, science in general and Nature in particular began to involve much more collaboration between researchers across borders. It was a big deal, for instance, when a foreign government banned Nature, as Nazi Germany did in 1938; German researchers had been using it as an important source of scientific news. The ban was furthermore covered in non-British media, such as The New York Times, indicating that the journal was internationally newsworthy. Such an increase in international readership meant more letters and articles sent to the editors, and by the 1950s, there was such a backlog that submissions needed to be held for six months or more. In the 1960s, the new editor John Maddox recognized this as a problem. He began his editorship by clearing the backlog, and even printed the date of submission along with each scientific paper to show everyone how quick Nature was at reviewing articles (“often within a month,” Baldwin’s book says). Clearly, Maddox thought that restoring the speedy reputation of the journal was important. He seems to have succeeded, for a time. As late as 1989, during a controversy around cold fusion, a Wall Street Journal article said that Nature was still fast: it was able to print papers “in as little as three weeks instead of the more usual lead time of six to twelve months for other scientific publications.” Thus, despite a dip in the middle of the century due to its popularity and international reach, speedy publication was still an important characteristic of Nature in the 1970s. A second — and so far permanent — decrease occurred more recently, perhaps as a result of prestige and the competition of near-instantaneous online platforms, but that’s another story. Network Effects As of 2022, scientists argue in public on Twitter, blogs, and other online platforms, like ResearchHub. In the 19th century, Twitter and ResearchHub hadn’t been invented [citation needed]. Fortunately, Nature was there. A network effect occurs when the value of a product comes primarily from the people who use it. If there are two competing telephone systems, the most valuable one is whichever has the most users (or at least the users you want to talk to). If you create an improved Twitter clone, then all its amazing features won’t do much if you don’t somehow manage to capture Twitter’s network of several million people. Likewise, Nature became an interesting journal to read and contribute to because it gained the attention of Britain’s scientific elite as the place to discuss big science questions. This role as a forum was a constant in Nature’s history, as Making Nature shows with several detailed accounts of debates that took place within the journal’s pages. Some examples: Controversies over the age of the Earth in the 1880s.
Inline links: this paper, a fancy prize for services to humanity, https://press.uchicago.edu/ucp/books/book/chicago/M/bo20298849.html, https://substackcdn.com/image/fetch/$s_!oY23!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F99a28e6f-d976-477a-8d14-f47510a23908_200x300.jpeg, https://substackcdn.com/image/fetch/$s_!glJ9!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2F873e6e2d-15a6-4b31-954b-f24fcd5e0e23_794x1024.jpeg, more than 15,000 letters, https://en.wikipedia.org/wiki/The_Athenaeum_(British_magazine), took many years, https://substackcdn.com/image/fetch/$s_!GYj8!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fa4f03221-7d79-42f6-bf6c-35d90fe3f7e5_1142x1600.jpeg, revealed, reports, ResearchHub
Lockyer had a cushy job as a civil servant in the British government, but dabbled in astronomy in his spare time. In the 19th century, dabbling in astronomy in your spare time could be an intellectually productive hobby: the line between professional and amateur science was blurrier then, and it wasn’t hard to contribute original research even without formal training. During the 1860s, Lockyer published several papers on astronomical observations, the most consequential of which might be the co-discovery and naming of the element helium, from his studies of the sun. His reputation grew among the “men of science” (as scientists called themselves then) of Victorian Britain, and he was soon elected to the Royal Society. But astronomy was an expense, not a source of income. Lockyer routinely supplemented his government job by writing nonspecialist scientific articles and books for a lay audience. Then, one day, he had an idea for a new kind of publication. It would be a weekly periodical to disseminate scientific knowledge to the broader public — but unlike the other periodicals that existed at the time, it would be written by the prominent men of science themselves. It would have a simple, evocative name: Nature. Lockyer summarized the two aims of Nature like this: FIRST, to place before the general public the grand results of Scientific Work and Scientific Discovery, and to urge the claims of Science to a more general recognition in Education and in Daily Life; And, SECONDLY, to aid Scientific men themselves, by giving early information of all advances made in any branch of Natural knowledge throughout the world, and by affording them an opportunity of discussing the various Scientific questions which arise from time to time. In other words (and getting rid of the old-fashioned capitalization of random adjectives and nouns), Nature was meant to do two things: communication from scientists to the public, and communication among scientists. It was an interesting idea. It was also a new one; until then the two aims had been separate. Recall that scientific journals have existed since 1665. During their first two hundred years, they primarily served to record the meetings of learned societies. The Philosophical Transactions of the Royal Society were originally just that: summaries of whatever “philosophical” questions were discussed at the Royal Society. Aside from journals, specialized books were common and were in fact the higher-status way to communicate science in Victorian Britain. Charles Darwin’s On the Origins of Species, published in 1859, is the most famous example. Informal correspondence between scientists was also a major, but private, channel: Darwin wrote more than 15,000 letters in his lifetime, enough to fill 30 volumes. With the exception of some books, none of the above were intended for laypeople. Educated non-scientists (professionals, clergymen, statesmen, etc.) instead got their science news from generalist or literary periodicals such as the Athenaeum magazine. The articles in those publications were not written by specialists, but by journalists and dilettantes. Lockyer’s view, shared with his close supporter Thomas Huxley — a biologist known for defending Darwinian evolution — was that they were riddled with errors and theological overtones. It would be better, they thought, if scientists did the work of communicating their research themselves. It was bold of Lockyer and Huxley to assume that scientists would be interested in doing this communication work. They weren’t. Almost immediately after Nature was founded, its contributors ignored the popularization part (“not a high-status undertaking,” Baldwin’s book says) and focused on the intra-science communication part. They did write summaries and abstracts of their own research, as Lockyer had intended, but they expected that their readers would be other men of science. Within three years, the educated laypeople who were Lockyer’s target audience were complaining that they could no longer understand the contents. Thus the first of Nature’s two aims was met mostly with failure. Fortunately, this was balanced out by unexpected success at the second aim. Scientists did actually enjoy writing for Lockyer’s magazine, in large part because it was published weekly. They found that writing a summary of their own research in Nature was an excellent way to share their results quickly and gain attention from other scientists. Books were slow; Darwin took many years to write and publish On the Origin of Species, for instance. The journals of scientific societies were slow; you had to wait for a meeting to take place and then for the meeting’s “transactions” to be published. Private correspondence was fast, but it wasn’t public. Through publication speed, as well as other factors as we’ll see below, Nature filled a niche in the ecosystem. It was the Twitter of 19th-century British science. Soon enough, this model would be copied, most notably by the journal Science in 1880. According to its first editor, Science was explicitly meant to, “in the United States, take the position which ‘Nature’ so ably occupies in England.” In just a few years, Nature had disrupted scientific publishing and established itself as a useful and unique institution of science, recognized by specialists both in the UK and abroad. First page of the first edition of Nature, 4 November 1869 II. One Hundred Years of Building a Reputation Despite its popularity, Nature didn’t become prestigious overnight. Far from it, in fact. Making Nature often reminds us that the journal spent most of its history as a low-grade publication where anything could be printed quickly, as long as it was factually correct. (This was ensured by basic checks from the editorial team; Nature articles were not consistently peer-reviewed until the 1970s.) As late as the 1960s, a researcher publishing a preliminary report in Nature was expected to follow up with a longer paper “in a more serious journal.” In other words, Nature delivered quick and cheap distribution, not luxury brand approval. This changed about fifty years ago, as we’ll see in Part III. But to understand what happened then, we first need to examine the characteristics of the journal in the roughly 100-year period from its early days until prestige took over, starting with a deeper look into publication speed. Publication Speed John Maddox, editor of Nature in the late 20th century, said that “one of Nature’s greatest early assets was the speed of the Royal Mail.” You could write to Nature, be published within a week, and read the replies to your communication within two weeks. This was state-of-the-art communication tech! Consider how many times publication speed is mentioned throughout the first half of the book (emphasis mine): What made Nature unique was, in large part, its ability to act as a venue for . . . discussions via its correspondence columns and its weekly publication schedule. (p. 8) Many British men of science found that one of the fastest ways to bring a scientific issue or idea to their fellow researchers’ attention was to send a communication to Nature. (p. 39) Unlike the literary periodicals, there was almost no delay between the submission of a piece and its appearance in the journal. (p. 63) A second reason Nature’s speed of publication would have been compelling to men of science is that getting one’s work into print quickly had become an increasingly essential part of establishing priority for a scientific finding or theory. (p. 65) Scientific weeklies [such as Nature] played a unique role in researchers’ publishing strategies at the end of the nineteenth century by offering researchers a forum where short articles could be printed quickly. (p. 105) Both the Proceedings [of the Royal Society of London] and the Philosophical Magazine had significant lag times between submission and publication . . ., which made Nature and its weekly turnaround uniquely valuable for the priority-conscious Rutherford. (p. 109) [Rutherford] sent his most interesting experimental results [to Nature] immediately, both as a way of keeping his colleagues updated on his work and as insurance against being scooped as he had in 1899. (p. 112) These quotes highlight two distinct reasons why speed was important. The first, as I hinted at earlier, was Nature’s role as the аcademic social media of its time. It was simply the best way to have discussions about scientific topics — or science itself — that could, unlike private correspondence, reach a large audience. More on this in the next section. The second reason, as shown by the mentions of physicist Ernest Rutherford, was establishing priority. Today we take for granted that being the first to publish new ideas or results is important, but in the 19th century this was less clear. To bring up Darwin as an example again, he kept his thoughts on evolution private for many years, because he wanted to make sure his argument was sound before he submitted it to the public (although he did eventually sense the urgency of publishing the theory before Alfred Russel Wallace did). But as science became professionalized, “not being scooped” became more and more crucial, and the weekly Nature was a good tool to avoid that. All this talk of speed may surprise anyone who has recently submitted a paper to Nature. In 2016, an analysis revealed that the median time for Nature to review a paper was 150 days, i.e. 5 months, up from 85 days a decade earlier. Nature itself reports, for the year 2020, a median time of 226 days between submission and acceptance. We’re a long way from “less than a week.” Why was there a decrease in publication speed? As we might expect, the reason was Nature’s growing popularity, especially among the international scientific community. At least, that’s what happened the first time there was a slowdown, in the mid-20th century. Early on, Nature was a journal for and by British scientists. But in the first half of the 20th century, science in general and Nature in particular began to involve much more collaboration between researchers across borders. It was a big deal, for instance, when a foreign government banned Nature, as Nazi Germany did in 1938; German researchers had been using it as an important source of scientific news. The ban was furthermore covered in non-British media, such as The New York Times, indicating that the journal was internationally newsworthy. Such an increase in international readership meant more letters and articles sent to the editors, and by the 1950s, there was such a backlog that submissions needed to be held for six months or more. In the 1960s, the new editor John Maddox recognized this as a problem. He began his editorship by clearing the backlog, and even printed the date of submission along with each scientific paper to show everyone how quick Nature was at reviewing articles (“often within a month,” Baldwin’s book says). Clearly, Maddox thought that restoring the speedy reputation of the journal was important. He seems to have succeeded, for a time. As late as 1989, during a controversy around cold fusion, a Wall Street Journal article said that Nature was still fast: it was able to print papers “in as little as three weeks instead of the more usual lead time of six to twelve months for other scientific publications.” Thus, despite a dip in the middle of the century due to its popularity and international reach, speedy publication was still an important characteristic of Nature in the 1970s. A second — and so far permanent — decrease occurred more recently, perhaps as a result of prestige and the competition of near-instantaneous online platforms, but that’s another story. Network Effects As of 2022, scientists argue in public on Twitter, blogs, and other online platforms, like ResearchHub. In the 19th century, Twitter and ResearchHub hadn’t been invented [citation needed]. Fortunately, Nature was there. A network effect occurs when the value of a product comes primarily from the people who use it. If there are two competing telephone systems, the most valuable one is whichever has the most users (or at least the users you want to talk to). If you create an improved Twitter clone, then all its amazing features won’t do much if you don’t somehow manage to capture Twitter’s network of several million people. Likewise, Nature became an interesting journal to read and contribute to because it gained the attention of Britain’s scientific elite as the place to discuss big science questions. This role as a forum was a constant in Nature’s history, as Making Nature shows with several detailed accounts of debates that took place within the journal’s pages. Some examples: Controversies over the age of the Earth in the 1880s.
Inline links: more than 15,000 letters, https://en.wikipedia.org/wiki/The_Athenaeum_(British_magazine), took many years, https://substackcdn.com/image/fetch/$s_!GYj8!,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fbucketeer-e05bbc84-baa3-437e-9518-adb32be77984.s3.amazonaws.com%2Fpublic%2Fimages%2Fa4f03221-7d79-42f6-bf6c-35d90fe3f7e5_1142x1600.jpeg, revealed, reports, ResearchHub
Now, what does the released dopamine do? In PFC (via the mesocortical pathway), it draws attentional resources to the surprising stimulus and its plausible causes, gating out the processing of other, less relevant stimuli. Simultaneously, in NAc, it strengthens connections between PFC inputs and the endorphin-releasing cells, thereby wiring together the hedonic features of the reward and the sensory features of any cues predictive of it. This imbues the cue with the ability to release the GABAergic brake on VTA DA neurons all by itself. Phenomenologically, it results in us "liking" the cue as much (or nearly as much) as we like the reward (this is what allows, e.g., animal trainers to reinforce behavior with only the sound of a clicker that has previously been paired with food).
One neuroscientific perspective on this is that in order for dopamine to track reward prediction *error* (RPE), it is logically necessary that some other piece of neural circuitry track reward prediction *per se*, often called "value." Those of us who think that dopamine is computing RPE on a moment-by-moment basis (the first derivative of value; see Kim, Malik et al., Cell, 2020) therefore generally also believe that some other part of the brain, especially the ventral striatum (aka nucleus accumbens) and perhaps also the prefrontal cortex, maintains an estimate of value that gets updated by dopamine. And indeed, there are dozens of papers reporting that neural firing in these brain regions correlate with value over and above RPE.
I think this explanation differs from the one you offered because rather than seek some other neuromodulator to account for the "companionate love” phase of a relationship, you can just consider that phase to be the psychological correlate of the brain's internal value estimate as it is instantiated in this cortical/striatal circuitry. Though I certainly wouldn't rule out other options, especially intracellular mechanisms in these areas, because neural firing on these very long timescales is dubious.
First, these researchers needed to design a genetic construct. What's a construct, you ask? It's a carefully engineered piece of DNA that harnesses circular plasmids (tiny rings of DNA naturally found in bacteria) to introduce foreign genes into mammalian cells. Through a painstaking process called sub-cloning, equal parts molecular biology and divination, they managed to insert into their mouse a human APP gene carrying the mutation found in families with high rates of early-onset Alzheimer's.
To be considered a valid Alzheimer’s model, the Games mouse needed to express human APP at levels high enough to cause Alzheimer's-like pathology. Previous attempts by other labs had yielded mice that showed little to no amyloid plaques. Scientists suspected that higher expression levels might overcome this hurdle. They introduced the PDGF-β promoter, a genetic “on switch” that controls when and where a gene is activated to drive high expression in neurons; they included introns in the construct to allow for alternative splicing, a process that enables cells to produce different versions of a protein, in this case ensuring expression of the full range of amyloid-beta peptides seen in human Alzheimer’s.
When the Games team finally (miraculously!) had a perfect construct, the next phase began: obtaining precisely timed mouse embryos. To make this transgenic mouse line, researchers needed to inject the transgene into single-cell fertilized embryos, prior to the first cell division event. It’s a very small needle, but only by threading it can you ensure that the transgene incorporates into the DNA of every dividing cell. Back when the study was conducted in the 1990s, the Games team had to rely on natural fertilization, meaning they needed female mice that had just ovulated and mated.
Impaired amyloid clearance due to having one or (much worse) two copies of ApoE4 [12], which is by far the most common genetic risk factor. The mechanism here may be a loss of function in microglia, a type of immune cell in the brain which helps clear plaques. [13]
Overproduction or reduced clearance due to microbial infection. Amyloid-β appears to be an antimicrobial peptide and will form plaques in response to infection. [2, 3] This explains various observations that have been used to support the “infectious hypothesis”, sometimes proposed as an alternative to the amyloid hypothesis. However, it can only explain a subset of cases and, as I argue below, is even then still mediated by amyloid via an “IATN” pathway: infection → amyloid → tau → neurodegeneration. In cases of increased production, cerebrospinal fluid (CSF) will show elevated amyloid. In cases of reduced clearance, amyloid will decrease in CSF. In all cases, however, PET scans will show elevated brain amyloid, usually at first mainly in “intrinsic connectivity networks” such as the default mode network [14–20], which experience brain activity even at rest. These neurons are the most active - which causes more production and possibly less opportunity for clearance - so they tend to be the first to suffer from a production/clearance imbalance. Over time, amyloid pathology spreads spatially throughout the brain. [14, 18] Aggregations of amyloid peptides induce more such aggregations. Some of our clearest evidence for this comes from growth hormone deficiency patients, who used to have cadaver-derived ground-up brain matter injected into their own brains to provide the missing hormones. If the ground-up brain matter was sourced from the corpse of an Alzheimer’s patient, the growth hormone deficiency patients would themselves develop Alzheimer’s at a young age, probably through prion-like spread of the misfolded proteins. [21, 22] After ∼15 years of preclinical spread, the pathology eventually covers the whole brain. [14, 18] While some subtle cognitive impairment may occur during this time, it is usually not severe enough to be clinically detectable from amyloid alone. Indeed, in both humans [23–30] and mice [31–35], the severity of neurodegeneration and cognitive deficits is not a good spatiotemporal match for the severity of amyloid pathology (rather, it is a good match for the severity of tau pathology; see next section for more). These facts are often suggested as evidence against the amyloid hypothesis. However, amyloid is causally upstream of tau, as I will argue below. Therefore, the existence of cognitively normal individuals with amyloid pathology is expected in the ATN model - but typically only for a few decades, before progression to the next stage. 2: Tau pathology (T) and neurodegeneration (N) Tauopathies are a range of prion-like diseases involving the tau protein [36], whose usual function is to assist in stabilizing microtubule structure. In a tauopathy, the tau protein misfolds, and induces other, nearby tau proteins to misfold into the same shape. [37–46]. Injecting nothing but misfolded tau fibrils into a mouse brain can recruit the endogenously-produced mouse tau into this pathology, which spreads far beyond the injection site, causing neurodegeneration wherever it goes. [35, 47–59] There are at least eight distinct ways the tau protein can misfold in human disease [36], and over a dozen distinct human tauopathies, each involving a specific one of those misfoldings. These include chronic traumatic encephalopathy, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, and Alzheimer’s disease, with the last by far the most common. Each of these five diseases has its own distinct tau fold. Most normal human beings eventually develop some tau pathology in adulthood, originating probably in the locus coeruleus [60–62], which is part of the brainstem. By middle age, some amount has usually spread to the hippocampus and entorhinal cortex in the medial temporal lobe, regions responsible for episodic memory. This is called primary age-related tauopathy (PART) [63], and has its own tau fold which is distinct from most tauopathies, but the same as Alzheimer’s. [36, 64] Usually, its local severity is mild and it doesn’t spread much beyond those regions. But with sufficient amyloid pathology, this “normal” tau pathology tends to both locally worsen and spread through the rest of the brain [65], becoming the tau pathology of Alzheimer’s. Some genetic risk factors such as ApoE, in addition to affecting the clearance of amyloid-β, also increase the brain’s susceptibility to this A → T pathology conversion [66, 67]. But this is a matter of degree, as sufficient amyloid pathology seems to virtually guarantee the transition: Every 10-centiloid increase in amyloid pathology for a cognitively normal individual increases by 2.7x the probability of a PET scan detecting pathological levels of tau within five years [68]. The only known cases where patients with extremely high amyloid levels can go significant amounts of time without developing tau pathology are a few individuals with extremely rare protective genes, known only from a few case studies, e.g. [69]. Even in these instances, the individuals will eventually succumb to the tau phase, suffering neural atrophy and dementia. [70] After it forms, the tau pathology no longer appears to require amyloid’s assistance to keep spreading (although amyloid may still accelerate it). This probably explains why existing anti-amyloid therapies have been only ∼30% effective in test patients, who are usually late in the amyloid → tau progression even if early in having symptomatic disease. Neurodegeneration follows tau pathology extremely closely in time and space, in humans as well as basically all animal models, and cognitive impairments match the functions of the affected regions. There are rare reports of advanced tau pathology without cognitive decline, often in people with protective ApoE2 alleles [71], but even then, systematic analysis finds that actual density of tau inclusions is highly predictive of cognitive impairment, and that these exceptional cases usually involve widespread but locally sparse pathology [66]. The regional distribution of tau pathology explains why the first symptom of Alzheimer’s is typically impaired memory; the first cortical sites affected are usually in regions involved in memory formation. As the pathology spreads, further regions are affected, until eventually all cognitive functions are affected. As with most other aspects of the disease, the high-level picture seems relatively clear but the exact cellular and molecular pathways are not well understood (though may involve an assist from the innate immune system, especially microglia and astrocytes. [13, 35, 72]) Early Alzheimer mouse models were amyloid-only, with extremely heavy overproduction of Aβ, much more than required to recapitulate the human disease, and apparently enough to cause detectable cognitive dysfunction. However, normal mice do not get age-related tauopathy, so an amyloid-only mouse model - while useful for investigating certain questions - is not a full Alzheimer’s disease model. Combined amyloid+tau pathology mouse models, which are transgenically modified and/or injected with misfolded human tau fibrils, display the property that the presence of amyloid pathology induces the worsening and spreading of tau pathology. This is also observed in vitro in human cells. How do we know the amyloid causes the tau? Researchers have measured the correlation in many ways, from the spatiotemporal timeline (tau pathology only begins locally worsening and spreading outside the medial temporal lobe once amyloid reaches sufficient severity) [65], [98], to causal mediation modeling in the human disease [26], [99–101], to causal intervention using in vitro human cell studies [54, 102] and animal models [35, 55], [103 – 113]. But also, giving people drugs that reduce amyloid levels also decreases tau pathology. [78, 80, 82] (I’ve left out or merely alluded to much other complexity, involving the innate immune system, lipid processing, and detailed molecular and cellular mechanisms, preferring to focus on the parts of the story which are crucial to deciding the causal role of amyloid, and for which I am aware of a satisfactory account from the literature. But I don’t intend to leave the impression that the above is all there is to Alzheimer’s disease, or that all cases progress in the same exact way.) The mechanistic claims I make the following two claims about amyloid-β’s role in Alzheimer’s: Amyloid deposits are a necessary (i.e. but-for) cause in all instances of Alzheimer dementia. That is, if someone has PET or CSF positivity for amyloid and tau pathologies, and the tau pathology involves the Alzheimer tau fold and made its first cortical appearance in the medial temporal lobe, and then they developed medial temporal volume loss + amnestic mild cognitive impairment + later dementia, then counterfactually, early enough (probably ∼15 years before clinical presentation) causal intervention solely to remove the amyloid deposits would have prevented almost all tau pathology and symptoms.
Inline links: below, probably through prion-like spread of the misfolded proteins, 10-centiloid, have been, the presence of amyloid pathology induces the worsening and spreading of tau pathology
The evidence that Aβ can potentiate or accelerate tau pathology (which itself is proximate to neurodegeneration), from studies in animal models, studies in human cells, the spatiotemporal disease course, causal mediation modeling of that disease course, and the tau biomarker effects from amyloid therapies.
Inline links: Aβ can potentiate or accelerate tau pathology