ARTICLE – The Paradox Institute
Developmental Biology
ZACHARY ELLIOT – 15 JANUARY 2022 – THE PARADOX INSTITUTE
Many often conflate two concepts in biology: how sex is defined versus how sex is determined. Conflating these two things, as we will see, can create absurd conclusions, so it is important we separate them out to accurately understand what male and female are and how they develop in the womb.
Defining sex: What are male and female?
Biologically, sex is defined with respect to gamete type.[1] Because there are only two gamete types, there are only two sexes.[2] The male sex is the phenotype that produces small gametes (sperm) and the female sex is the phenotype that produces large gametes (ova).[3] This applies to all species that reproduce through two gametes of differing size (anisogamy), and it includes humans.[4]
Based on this definition, we know whether an individual is male or female by looking at the structures that support the production (gonads) and release (genitalia) of either gamete type.[5] In other words, we look at whether the individual develops a body plan organized around small gametes or large gametes.[6] In humans, sex is binary and immutable. Individuals are either male or female throughout their entire life cycle.[7]
Determining sex: How does an individual become a male or female?
In humans, sex is determined by genes.[8] In biology, determining sex does not mean “observing” or “identifying sex” in the colloquial sense. Instead, determining sex is a technical term for the process by which genes trigger and regulate differentiation down the male or female path in the womb. This determines the structures that can support the production and release of either gamete type, and thus, the individual’s sex.[9]
There are many different sex determination mechanisms across species.[10] Humans and other mammals use genetic sex determination, where certain genes trigger male or female development, whereas reptiles often use temperature sex determination, where certain temperature values trigger male or female development.[11] In all these species, an individual’s sex is defined with respect to gamete type and identified by the structures that support the production and release of either gamete.
Thus, while there are various mechanisms that control male and female development, there are still only two endpoints: male and female.[12]
Why determining sex =/= defining sex
There’s two main reasons why the mechanisms that determine sex (like genes) are not the same thing as the definition of sex.
First, because sex determination mechanisms vary across species and across time, we cannot use them as the definition for the sex of individuals across species.
For example, mammals tend to use the X-Y chromosomal system, whereas birds tend to use the Z-W chromosomal system. Despite this difference in sex determination mechanisms, what unites male birds (ZZ) and male mammals (XY) is that they both develop the phenotypes that produce small gametes. And what unites female birds (ZW) and female mammals (XX) is that they both develop the phenotypes that produce large gametes.[13] The Z-W system in birds, like the X-Y system in humans, determines the development path the fetus will go down, and thus, their sex. Furthermore, sex determination mechanisms have changed across evolutionary history and continue to evolve depending upon specific conditions of the environment.
This shows us that sex determination mechanisms can be widely diverse across species yet result in the same outcome of males and females; it also shows us that sex determination mechanisms are not the same thing as sex.[14]
Second, because of developmental disorders, we cannot use sex determination mechanisms as the definition for the sex of individuals within humans and across species.
Almost always, the Y chromosome determines sex in humans: those with a Y chromosome develop as males, and those without the Y chromosome develop as females. Males usually have 46:XY and females usually have 46:XX.[15]
However, rare errors of cell division during meiosis can result in a translocation or mutation of genes within the chromosomes, and this can result in a sex opposite of what is expected from the chromosomes. For example, 1 in 20,000 births result in males with XX chromosomes.[16] This happens when the SRY gene (the male sex determining region on the Y chromosome) is translocated to an X chromosome during cell division in the father’s reproductive cells.[17] When the fetus is conceived, they receive XX [SRY]. SRY triggers a cascade of genes leading to male development: gonadal differentiation into testes, which then leads to the development of male internal and external genitalia.[18]
Though they cannot produce sperm, since this requires the AZF region from the Y chromosome, XX males are defined as male because they develop the phenotype that produces small gametes (determined by genetics).[19]
Another example for why we cannot use sex determination mechanisms like chromosomes as the definition of sex involves a rare case of a pregnant female with XXY chromosomes.[20] At conception, the lack of an SRY gene on the Y chromosome and the presence of two X chromosomes allowed transcription factors like WNT4 and RSPO1 to develop complete ovaries.[21] The lack of testes and the subsequent lack of anti-Mullerian hormone and testosterone then allowed for full development of female internal and external genitalia (oviducts, uterus, cervix, vagina, and vulva).
She is defined as female, despite the presence of the Y chromosome, because she developed the phenotype that produces large gametes (determined by genetics).
Both cases, and many others, reinforce the important distinction between the mechanisms that determine sex and sex itself. The sex development of both cases is charted below, showing how XX males develop as males and how the rare case of the XXY female developed as female.
Logical absurdities
Failing to distinguish between how sex is determined versus how sex is defined creates logical absurdities.
For example, if we define the XX male as female purely by absence of the Y chromosome, one must conclude that some females develop testes, a Wolffian structure, and a penis, and if we define the pregnant XXY female as male purely by the presence of the Y chromosome, one must conclude that some males can develop ovaries, a uterus, cervix, vagina, and a vulva, produce ova, and give birth.
In both instances, defining sex based on chromosomes alone (and not the genetically determined phenotype with respect to gamete type), results in absurd, self-contradictory logic. After all, how can a male develop a full female reproductive system and produce large gametes? And how can a female develop a full male reproductive system and produce small gametes? This would be like saying a piece of gold is iron and iron gold. However, gold is never iron and iron is never gold.
Likewise, males can never produce ova and give birth, and females can never produce sperm and impregnate. These reproductive functions are mutually exclusive.[22]
Unfortunately, this inaccurate logic—that absence of a Y chromosome is always female and presence of a Y chromosome always male—has immense ramifications if used by society.
For example, activists who argue that males can be females and females can be males would love to use this reasoning to deconstruct the definition of sex for sociopolitical purposes, and those who have atypical development may be relegated to categories they do not belong in: people with fully developed, genetically determined male bodies in female spaces and vice versa. Because of this, it’s best we maintain the distinction between the mechanisms that determine sex and the definition of sex.
Males and females are not defined by the mechanisms that develop them in the womb. They are defined by the phenotypes that produce either small or large gametes, respectively. For humans, this is determined by genetics. Defining sexes this way does not mean that sex is a spectrum or that one can change sex. One’s sex is determined at conception by the individual’s genetic profile, developed in utero, and immutable…