A new study reinforces the evidence for the safety and efficacy of the mRNA COVID-19 vaccines. That’s the TLDR, but let’s dive into the details.

Medical evidence is always rolled out in stages. First there is what we would consider preclinical evidence, or basic science. This could be initial uncontrolled clinical observations, or mechanistic animal or in vitro research. At some point we have sufficient evidence to generate a hypothesis that a specific treatment could be effective in treating a specific disease, enough to progress to human research. For FDA qualifying research, there are four specific phases. Phase I trials look at the safety of the intervention in usually healthy controls, while also answering basic questions and mechanism and effects. If there are no safety red-flags then the research progressed to a phase II trial, which look for preliminary evidence of efficacy, and further safety data. Again, if that data continues to look encouraging we can progress to a phase III trial, which is a larger and more rigorous trial designed to be definitive. Usually the FDA requires several phase III trials to grant approval of a drug for a specific indication. Then, once on the market there is phase IV trials, which look at data from more widespread use to confirm safety and effectiveness in the real world.

Looked at another way, we do research in the lab, then on dozens of people, then score to hundreds of people, then hundreds to thousands of people, and then finally on thousands to millions of people. Each step of the way we gain the ability to detect less and less common side effects in a broader set of people. Further, the types of evidence are designed to be complementary. Phase III trials, for example, are rigorously experimental, with highly defined populations with randomization to control as many variables as possible. Phase IV trials, on the other hand, are generally observational, designed to look at very large numbers of people in an uncontrolled setting – to determine how safe and effective the treatment is in real-world conditions.

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We have all likely had the experience that when we learn a task it becomes easier to learn a distinct but related task. Learning to cook one dish makes it easier to learn other dishes. Learning how to repair a radio helps you learn to repair other electronics. Even more abstractly – when you learn anything it can improve your ability to learn in general. This is partly because primate brains are very flexible – we can repurpose knowledge and skills to other areas. This is related to the fact that we are good at finding patterns and connections among disparate items. Language is also a good example of this – puns or witty linguistic humor is often based on making a connection between words in different contexts (I tried to tell a joke about chemistry, but there was no reaction).

Neuroscientists are always trying to understand what we call the “neuroanatomical correlates” of cognitive function – what part of the brain is responsible for specific tasks and abilities? There is no specific one-to-one correlation. I think the best current summary of how the brain is organized is that it is made of networks of modules. Modules are nodes in the brain that do specific processing, but they participate in multiple different networks or circuits, and may even have different functions in different networks. Networks can also be more or less widely distributed, with the higher cognitive functions tending to be more complex than specific simple tasks.

What, then, is happening in the brain when we exhibit this cognitive flexibility, repurposing elements of one learned task to help learn a new task? To address this question Princeton researchers looked at rhesus macaques. Specifically they wanted to know if primates engage in what is called “compositionality” – breaking down a task into specific components that can then be combined to perform the task. Those components can then be combined in new arrangements to compose a new task, like building with legos.

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