Fun article is you can get your eyes on it.
Several interesting and wise comments about doing biomedical research. The comment you might NOT expect given the tile (a bit of clever click-bait) is this:

>A common way to destroy a grant [application] in an NIH study section would be to suggest that ‘‘mice are unreliable models of X disease.’’ Just as I was uncomfortable with the negative tropes about translational work, a new pejorative rhetoric had emerged surrounding animal work."

This is so true. Almost all scientists who state confidently that THE MOUSE is not a good model for X or Y do not really know enough mouse genetics or biology to weigh in on this complex topic.

For good and bad reasons a great majority all mouse biomedical research (90% of more) is done using one fully inbred strain of mouse called C57BL/6 (or B6 for short). Almost all knockouts and transgenic mice are variants of B6. And this is the strain that was first sequenced. The good reason is genetic uniformity. The bad reason is also genetic uniformity.

As Kim mentions when someone says "‘mice are unreliable models of X disease’ they almost always mean that some disease manifestation does not occur in B6 mice. Yes, but in may and often does, occur in other types of mice. The only way to know for sure is to study 5 to 100 diverse strains of mice, of which one or many may have just the disease you are looking for. This is really not different the disease variation in humans.

Below is some of text from Kim's article, with the additional vital and true (but hardly surprising) conclusion that ENVIRONMENT matters too.

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Notwithstanding these fears, my lab continued to thread the needle of doing mouse work and coupling this to translational exploration in humans. In 2017, when we identified JAK1 in sensory neurons as a critical mediator of itch, Stuart Turvey, a highly accomplished physician-scientist who focuses on inborn errors of immunity, reached out to me to highlight their discovery of the first germline JAK1 gain-of-function (GoF) variant in patients.8 JAK1 is a primary conduit for numerous cytokines to signal within immune cells. Thus, these patients had multi-organ inflammatory pathology, including diseases like severe AD, asthma, and food allergy.

Stuart also pointed out to me that the children with this JAK1 GoF variant had itch that did not respond to even high-dose steroids. In fact, it was only when they received oral ruxolitinib (which inhibits both JAK1 and JAK2) that these children were relieved of their itching for the first time in their lives. He suggested to me that, consistent with our findings in mice, this was compelling evidence for JAK1 as a critical driver of itch in the nervous system in these patients.

Unbeknownst to Stuart, our email conversation inspired me to generate mice that conditionally expressed the exact variant of JAK1 he had discovered in his patients. Truthfully, there was no clear hypothesis. My trainees found this proposition very uninteresting because we had already mapped how JAK1 functions in itch nerves in the skin, and Stuart had already identified a syndrome caused by the mutation. To make matters worse, we made the wrong mice.

Instead of inserting the human JAK1 GoF variant exclusively in sensory nerves, a misunderstanding led to generating mice in which the JAK1 GoF variant was expressed in a germline fashion, just like in the patients. What was the point of reinventing a human disease in a mouse? This was the opposite of translational research. While serendipity is defined as unplanned fortune in science and understood to be a virtue, this was in many ways a misplanned misfortune. Nonetheless, I remained stubbornly persistent.

The JAK1 GoF mice spontaneously developed AD-like skin inflammation akin to what the patients had displayed. However, in contrast the children, they did not develop asthma. There were so many reasons to abandon the project. I made the wrong mouse, I had no clear hypothesis, and the phenotypes did not match. My lab came to the biting conclusion that humans are unreliable models of mouse disease.

However, this is where the story takes an unusual twist.Buried within the chaos was a biology that would not only explain why the children developed asthma while the mice did not but also reveal fundamental new neuroimmune mechanisms in the lung. In short, what we found was that for the mice to develop asthma-like disease, they had to be exposed to an allergen. However, in contrast to the conventional role of JAK1 as a mediator of inflammation in immune cells, we found that JAK1 within sensory neurons plays an anti-inflammatory function.

Masato Tamari, a very talented pediatric allergist and postdoctoral fellow in my lab, was unde- terred by the challenges and decided to persist. He found that while the JAK1 GoF mice spon- taneously developed skin inflammation, unlike the patients, they did not spontaneously develop asthma-like disease.

We then hypothesized that a major limitation in studying lab mice compared to humans is their lack of exposure to environmental allergens. Indeed, upon challenge withAlternaria alternata, an asthma-associated allergen, these mice exhibited enhanced susceptibility to allergic lung inflammation.

Thus, the mystery was solved, and we could have simply stopped here. The conclusion was that of the classic scenario where genes interact with the environment to drive a clinical phenotype. However, we decided to persist and dig deeper.