Homosexuality is pretty cool biology wise. The markers that predetermine it are predictable in the womb and seem to be an actual evolutionary trait. Which I was really surprised to learn. If something proves transgender stuff is similar, that’d be very interesting.

The physiological differences between men and women are dictated by the ratios of specific types of hormones during development: estrogens for female traits, androgens for male traits. The handful of genes responsible for these mutate reasonably commonly with fairly neutral effect, but more significant mutations can cause inequal development of male and female physiology. Mutations to the srY gene, a keystone of gender expression, can also cause these sorts of effects.

Some examples of such effects include:

• Individuals with XX chromosomes, but male physical features, caused by the srY gene migrating to an X chromosome
• Swyer Syndrome, where an individual has XY chromosomes, but the srY gene migrated to the X chromosome. This causes them to develop female physical features, but nonfunctional gonads—this means they will not naturally experience puberty, among other issues. (The normal treatment is hormone replacement therapy, because the problem is that their gonads aren’t able to produce the right hormones on their own.)
• Androgen insensitivity syndrome, wherein male physiology, especially sex organs, only develops partially or not at all.

Additionally, hormones are spread around by regular, chaotic fluid dynamics, and fetuses don’t grow in a vacuum, but rather inside a sac inside another person who is producing their own hormones. Therefore, it’s rather unlikely all parts of the body will actually receive equal ratios of androgens and estrogens - which can lead to, for instance, the brain developing in a structure and exhibity measurably more like the ‘typical’ female brain structure despite the individual’s physiology being overall male. There have been actual brain scans done of transgender individuals that identify this, AFAIK.

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I don’t understand how not feeling comfortable in your own skin isn’t an illness.

I’d like to probe this with examples of other things that can be reasonably accurately described as some version of “not feeling comfortable in your own skin” (I’d like to be clear that these are examples for you to assess this idea with—I think there are reasonable arguments for and against these being illnesses. What I’d like to know is if these examples that would reasonably be considered an illness under that definition actually align with what you think an illness is?):

• Is disliking being overweight an illness? What about being underweight?

• If you’re born missing a limb, is it an illness if you want a prosthetic?

• If you don’t like your voice, is wanting to do voice training illness? What about greying hair? Or hair loss?

From another angle, given the problem is a mismatch between mind and body, is changing the mind (i.e. the person) better than changing the body? Even in terms of simple capabilities, changing the body is much easier and more doable for modern medicine than changing the mind. We’ve been developing antidepressants, for example, for 50 years, and they still can cause depression as a side effect.