A Response to Nature’s ‘Sex Redefined’
A scientific rebuttal of Nature’s famous piece, “Sex Redefined: The Idea of Two Sexes Is Overly Simplistic.”
This rebuttal appears in Binary, a book published by the Paradox Institute.
All claims are directly cited with peer-reviewed biology literature. Refer to the citation number and see the bibliography at the end for the full citation.
Redefining the sexes requires a rejection of fundamental observations from biology, whether it is the universality of male and female as distinct reproductive functions to their differentiation and development in the womb. Sex spectrum proponents have found the most effective way to reject this evidence: take advantage of biology’s complexity.
The primary strategy for redefining the sexes uses complexity in biology to obfuscate the simple reality of male and female. No other piece employs this strategy better than Claire Ainsworth’s “Sex Redefined.” Published in Nature Magazine in 2015, the piece is the gold standard for how the complexities of scientific findings can be employed for pseudoscientific political ideologies. Ainsworth explores a variety of rare medical conditions to prove that the “idea of two sexes is simplistic” and to deconstruct and redefine male and female. To understand her argument and how to respond, let’s explore the piece with peer-reviewed research from evolutionary and developmental biology.
The first step is defining the sexes. There is no definition of male and female provided in “Sex Redefined,” so for clarity, we must show the biological definition of male and female:
Universal biological definition: The male sex is the phenotype that produces the smaller gametes (sperm), and the female sex is the phenotype that produces the larger gametes (eggs).[1]
The definition applies across all species that reproduce through gametes of differing size (anisogamy); it is therefore the universal biological definition for male and female. Ainsworth’s piece “Sex Redefined” fails to provide this definition and any definition at all. Instead, she focuses on the variation in structure (phenotype) within males and females, detaching it from its relationship to function (gamete production). In other words, she looks at how people’s bodies look while never relating that to what sex-based function those bodies serve. This allows her to claim that sex exists on a spectrum.
Like all common sex spectrum arguments, “Sex Redefined” detaches sex from its role in reproduction and uses complex medical conditions as tools to deconstruct male and female and replace these categories with subjective identity. This requires a fundamental redefinition of male and female from reproductive categories into mere mixtures of independent characteristics.
For most of the piece, Ainsworth utilizes the sex spectrum’s biological principle (sex exists on a continuum between male and female) to argue that the categories of male and female are overly simplistic and need redefining. She does this by:
Detaching male and female from their roles in reproduction.
Using disorders of sex development as exceptions to male and female.
Conflating sex determination mechanisms with sex.
To analyze her argument, let’s breakdown the examples she uses.
Genetics
Advanced DNA sequencing has uncovered the wide range of gene variation that can impact people’s bodies, both in typical individuals and in those with DSDs. Ainsworth uses this genetic variation as her first tool in the sex spectrum arsenal by conflating the mechanisms that determine and develop sex with sex itself.
Case 1: A pregnant woman has an unusual karyotype.
In 2010, a pregnant woman visited a clinic at the Royal Melbourne Hospital in Australia to scan for chromosomal abnormalities. There she discovered her own chromosomal makeup was unusual: one set of her own cells carried 45:X, typical of Turner’s Syndrome in females, and another set of her cells carried 46:XY, the typical for males. She had a mosaic karyotype.[2]
Ainsworth claims this case shows sex is more complicated than male or female. But this is a category error: conflating chromosomes with sex. The mother developed the large gamete phenotype, and she was pregnant with her third child; it is rather safe to say she’s female.[3] It therefore does not prove Ainsworth’s point that the idea of “two sexes” is “simplistic.” Does it show us that chromosomal abnormalities can occur? Yes. Does it show us the amazing and variable world of genetics? Yes.
But does it show us that male and female are unreliable categories? No. The fact that the patient is female, even with her unusual karyotype, reinforces the binary. So, why the confusion?
Case 2: Mismatch of chromosomes and phenotype.
Ainsworth writes that “gene mutations affecting gonad development can result in a person with XY chromosomes developing typically female characteristics, whereas alterations in hormone signaling can cause XX individuals to develop along male lines.”
It is true that, rarely, males may develop with XX chromosomes and females may develop with XY chromosomes, opposite of what is expected from the chromosomes.[4] But sex spectrum proponents interpret this mismatch of chromosomes and phenotype as evidence of a spectrum between male and female. It’s not. This is a conflation of sex determination mechanisms with sex.
The only reason we can identify these individuals as male or female is because we already know what sexes are irrespective of chromosomes.[5] Males with XX chromosomes are male because they develop the small gamete phenotype, and females with XY chromosomes are female because they develop the large gamete phenotype.[6]
Case 3: Translocation or mutation of sex-determining genes.
Ainsworth presents a variety of genes that, when moved onto different chromosomes or mutated, can cause a change in the development path of the fetus from what’s expected by their chromosomes. These include the SRY and SOX9 genes for testes development and WNT4 and RSPO1 for ovarian development.[7]
First, take the SRY gene. It’s the sex-determining region on the Y chromosome, and the master switch for male sex determination by initiating gonadal differentiation into testes.[8] Sometimes, however, SRY can translocate or mutate.
Three examples show us how important this gene is for male sex differentiation and development:
On very rare occasions, a fetus may develop with two X chromosomes and one Y, or three Xs and one Y, or even four Xs and one Y. Despite the extra X chromosomes, all these cases develop as males thanks to the presence of SRY on the Y chromosome.
Sometimes, a translocation of the SRY gene results in it being placed on an X chromosome in a fetus with two X chromosomes. Thanks to the presence of SRY, the fetus develops as a male despite having no Y chromosome.
In exceptional cases, a fetus may develop as a female with an XY karyotype. Because the SRY gene remains inactive, they develop as females.[9]
Second, take the WNT4 gene. WNT4 plays an essential role in promoting ovarian development. With a duplication of WNT4 in XY fetuses, testes development is suppressed by undermining the role of the SRY gene, inhibiting its downstream target, SOX9.[10] In its place, ovarian differentiation and development is promoted and the fetus develops as a female.
Thus, cases of SRY or WNT4 mutation show us that sex development requires a precise sequence of activating and repressing factors. Alter this sequence, and the fetus may develop as the opposite sex compared to what is expected from the chromosomes.
Ainsworth presents these cases to try and claim that the idea of two sexes is simplistic, because the process of sex determination can be complex and variable. But whether it’s through the activation or suppression of certain genes, or even mutations or translocations onto other chromosomes, these complex genetic networks produce incredibly simple results: males and females.
Because male and female sex determining genes express themselves antagonistically by inhibiting genes involved in the opposite sex pathway, such genes cannot promote both sex pathways at the same time.[11] Thus, cases of SRY and WNT4 translocation, mutation, or duplication consistently result in males or females, not both nor in between.
Hormones
Decades of research in biology has shown the importance of sex hormones for the development of the fetus. Androgens like testosterone and dihydrotestosterone play a major role in masculinizing the male fetus during sex development, building the internal and external genitalia. These structures will help carry and release sperm.
Alter this system, however, such as reducing the amount of testosterone or blocking its reception, and there will be atypical results. Ainsworth uses this diversity in hormonal profiles to claim that sex exists on a spectrum. Let’s analyze three cases she uses.
Case 4: Androgen receptor gene mutation.
Ainsworth uses a condition called Complete Androgen Insensitivity Syndrome to claim that sex exists on a spectrum. But a closer look at this condition shows us the importance of the androgen receptors for male sex development; it does not make the categories of male and female unreliable.
CAIS causes a 46:XY fetus to develop a female body structure despite having internal testicular tissue. A mutation in the androgen receptor gene on the X chromosome halts the body’s ability to respond to testosterone produced from the testes.
With no ability to respond to T, the testes do not develop further (remaining in the abdomen),[12] the germ cells never differentiate into sperm,[13] the primordial internal genitalia disintegrate, and the external genitalia develops into a vulva and lower vagina.[14] Testosterone produced by the testes is then converted into estrogen, and the body feminizes.[15] Girls and women with CAIS usually do not develop fallopian tubes or a uterus because the testes produce anti-Mullerian hormone (AMH), and AMH causes these female structures to disintegrate before they can develop further.
However, because the bodies of those with CAIS cannot respond to any androgen, there are many consequences. First, they are infertile: they cannot produce sperm from their internal testicular tissue, and since they do not have ovaries, they cannot produce ova. Second, because of their phenotype determined by the AR gene mutation, they are observed at birth as females, raised as females, and even go through puberty as females (just without menstruation).
Because of the absence of T reception and the conversion of the testosterone into estrogen, women with CAIS tend to have female-typical bone and muscle structures, develop breasts at puberty, and have female-typical psychological profiles, such as sexual attraction to males.
Ainsworth and sex spectrum proponents think that CAIS somehow proves that male and female are unreliable categories. But if male and female did not exist, CAIS would not exist. The only reason we can understand such a condition is because male and female are real, biological categories, produced by complex systems of genes and hormones which work together to form the two reproductive roles. CAIS does not undermine this system but rather shows us the underlying mechanisms (like testosterone and androgen receptors) that help produce the binary system of sex.
Case 5: Atypical development of genitalia from hormones.
Infants are sometimes born with congenital conditions that cause the external genitalia to look different than what’s typical. Ainsworth brings up Congenital Adrenal Hyperplasia (CAH), a condition that affects both males and females. In 46:XX females with CAH, a mutation in the CYP21A2 gene leads to an overproduction of androgens like testosterone in the adrenal glands, and the female fetus, who develops ovaries, uterus, cervix, and vagina, is exposed to this higher level of androgens.[16]
Because the external genitalia is highly sensitive to androgen exposure,[17] the clitoris and labia of the female fetus can look slightly masculinized (longer clitoris, fused labia). This does not mean they are suddenly males, however. As discussed in this book’s response to SciShow’s video “There Are More Than Two Human Sexes,” girls and women with CAH are female because they develop the large gamete phenotype.
The fact some genitalia look different from the norm does not mean that sex is a spectrum, that people can have both a penis and a vagina, or that sex can be changed through hormones. It simply means that, within males and within females, there are differences in the external appearance of genitalia, some differences from typical variation and others from disorders. In other words, there are differences in sex characteristics, not variation of sex.
Using girls and women with CAH, or other people with developmental conditions, to argue that sex is a spectrum is not just scientifically inaccurate, but it also reinforces stereotyped ideals of male and female bodies. In the sex spectrum, if your genitalia is more masculinized for a female, you’re suddenly not female or exist “in between” the sexes. For sex spectrum proponents who say they are against ‘othering’ people for being different, they should stop claiming people with atypical genital morphology are not males or females.
Case 6: A uterus found in a fertile male.
In the hormone category, Ainsworth concludes by mentioning a vanishingly rare case: a 70-year-old man who fathered children went to the hospital for a hernia, when the doctors found a uterus in his abdomen.[18] Sex spectrum proponents claim that this case proves sex is a spectrum, and that the categories of male and female are unreliable.
However, this male with a uterus did not develop the large gamete phenotype. Instead, he developed testes, internal sperm transportation systems, and a penis. Not only this, but he was fertile and fathered children with his sperm. So, why the uterus? The vestigial uterus had developed due to a gene mutation, causing anti-Müllerian hormone to not be fully produced, which allowed parts of the Müllerian structure to remain, leaving the vestigial uterus.[19]
This disorder is called Persistent Müllerian Duct Syndrome, where parts of the internal female reproductive structures remain in a male with typical chromosomes and a typical phenotype. Males with PMDS cannot fulfill the female role because their phenotypes are organized around small gametes, not large gametes.
The case does not show male and female are unreliable. After all, this male produced sperm and fathered children! Rather, it shows us the importance of anti-Müllerian hormone in the disintegration of primordial female structures and the development of the male sex.[20] It shows us the various mechanisms at play in sex development, but it does not change or challenge male and female.
Cells
After the genetics and hormone categories, Ainsworth moves to cells. Inside the cell’s nucleus is your genome, contained within chromosomes. Atypical cell composition within the body, such as having cells with a genetic makeup different from other cells in the body, can result in developmental disorders.
Differences in the genetic composition of cells, outside of the typical person whose diploid cells are all 46:XX or 46:XY, has led sex spectrum proponents to claim that cell variation shows male and female are unreliable categories. This is once again a conflation of two concepts: sex determination mechanisms and sex itself.
Case 7. Mosaic cells as evidence that sex is not binary.
Rarely, some people are born with a mix of genetically different cells in their body, caused by the development of a single fertilized egg with different genetic makeups. Some cells have a certain number or type of chromosomes, whereas others have another number or type of chromosomes. This is called mosaicism.[21]
And yet, using mosaicism to argue that sex is not binary is a category error. It conflates sex determination mechanisms (genes) with sex (reproductive role). A patchwork of genetically different cells does not mean the person is not male or female.
For example, if we recall from the beginning of this chapter, with the case study of the pregnant woman with a predominately XY karyotype, we see that this woman has mosaicism: some of her cells are XX, and others are XY. Despite this, she did not develop as a male or “in between.” She developed a large gamete phenotype, able to support ova, conceive, and give birth. Thus, having a unique set of chromosomes does not mean you will have a unique sex.
Unusual karyotypes like mosaicism can certainly affect the body’s physiology and how it may respond to factors like disease, and so it’s important to study the full range of possible differences within male and female bodies. But this does not mean rejecting that the two sexes are real reproductive categories with distinct phenotypes.
Case 8. Cells crossing the placenta into the mother’s body.
Sometimes, the cells within a fetus can cross the structure that provides oxygen and nutrients to the baby during gestation (the placenta), and some of them can enter the mother’s bloodstream (a phenomenon known as microchimerism).[22]
Fetal cells can be in maternal tissues both during and after pregnancy, and these cells can potentially act as reparative stem cells, helping the body respond to tissue injury.[23] These cells have been found in women’s bodies for as long as three decades. Microchimerism may in part be one of the many factors for why women, on average, live longer than men. It is not, however, as Ainsworth argues, evidence male and female are unreliable categories.
She writes, “This type of work has further blurred the sex divide, because it means that men often carry cells from their mothers, and women who have been pregnant with a male fetus can carry a smattering of its discarded cells.”
There is one major problem with Ainsworth’s statement: to think having a small minority of cells from another person’s body in yours suddenly “blurs the sex divide” is to assume that for male and female to exist, they must be “pure” forms with no variation, nothing for them to share in common nor any diversity within the two. But this is an absurd conclusion. Male and female are real, reliable reproductive categories with distinct phenotypes. Atypical cells inside the body do not change this.
A man with a minority of cells from his mother does not suddenly become “intersex.” A mother with a minority of cells from her fetus does not either. He’s male because he developed the small gamete phenotype. She’s female because she developed the large gamete phenotype.
Neither of these microchimeric cases call into question what male and female are. To say they do is to ironically reject the natural diversity within males and females and reinforce a strict, black and white binary that does not allow for variation within the two categories. In contrast, the true sex binary understands there are only two reproductive roles (male and female) with plenty of variation in anatomy, physiology, and behavior.
Case 9. XX and XY cells behave differently.
In the last case, Ainsworth discusses how sex difference research revealed cells with XX and cells with XY behave differently independent from sex hormones.
For example, a double dose of the X chromosome impacts the body’s response to stress. She writes, “The next challenge, says Arnold, is to uncover the mechanisms. His team is studying the handful of X-chromosome genes now known to be more active in females than in males.”
Suddenly, Ainsworth is comfortable using the terms male and female as if they are definable categories, ignoring everything she has argued so far, including the very title of her piece, “Sex Redefined.” Why? If she claims the sexes are blurry categories, then how do we know X-chromosome genes are more active in females? How do know what a female is in the first place? Basic contradictions like these are scattered throughout the sex spectrum argument, but they are never addressed.
Whether it is Genetics, Hormones, or Cells, Claire Ainsworth argues that sex exists on a continuum, that congenital disorders prove male and female are unreliable categories, and that the complexity of sex determination mechanisms are proof of the sex spectrum. The problem, however, is that male and female have a universal biological meaning which applies both within humans and across a vast array of species.
This universal definition of male and female will not work for Ainsworth, however, because she does not view the sexes as functional mechanisms. For her, each person can be reduced to singular traits along the spectrum: if you do not fit the platonic ideal of male and female (for example, that males must always have XY and females must always have XX), then you are not male or female.
This idea, sex as a mix of traits detached from reproduction, is the foothold for the deconstruction of male and female by sex spectrum theorists and activists. Rare developmental disorders are used as the leverage to open the door. Ainsworth uses both strategies.
These strategies fail to validate the sex spectrum argument, however. Across genetics, hormones, and cells, we can clearly identify male and female by identifying the structures that support the production (gonads) and transportation (genitalia) of either gamete type. This is something Ainsworth never mentions, because she wants to conflate the diversity in people’s bodies and the complexity of genetics with sex itself to make the categories of male and female seem undefinable.
While it is true the mechanisms involved in sex determination are complex, and that people’s bodies can be wildly different in appearance, the result is simple and consistent: male or female, two distinct phenotypes organized around either small or large gametes. Rather than showing us the “idea of two sexes is simplistic,” these rare cases show us that sex development can be simultaneously complex in its process and simplistic in its end result. In other words, there are many potential paths for developing as a male or female, but there are only two endpoints, thus reinforcing the binary system of sex.
As much as it may seem from the surface, Ainsworth’s piece is not really about biology. It is about using biology as a tool to convince the reader of her own political conclusions: that male and female are unreliable categories, and that gender identity, an internal sense of self, is the most accurate marker of sex.
Ainsworth reveals this at the end of her piece, quoting a doctor who treats infants with DSDs: “My feeling is that since there is not one biological parameter that takes over every other parameter [social principle], at the end of the day, gender identity seems to be the most reasonable parameter [political principle].”
“In other words,” Ainsworth concludes, “if you want to know whether someone is male or female, it may be just to ask.”
It may be just best to ask? Is that really the most reasonable parameter of sex? That does not sound very scientific. But that is a feature, not a bug, in the sex spectrum argument, which requires obscuring sex for sociopolitical purposes.
Ainsworth’s piece is not about redefining the sexes. If it was, she would have given a re-definition of sex. But she did not, let alone any definition.
Instead, Sex Redefined is about obfuscation and replacement: first, obscuring sex by overwhelming the reader with a vast array of scientific information irrelevant to the argument, and second, replacing sex with the completely unrelated political ideology of gender identity. Sex Replaced would have been a more appropriate title.
After the article was published, a Twitter user asked Claire Ainsworth, “In your piece, ‘Sex Redefined,’ are you making the claim there are more than two sexes?” Ainsworth then responded, “No, not at all. Two sexes, with a continuum of variation in anatomy / physiology.”
It is clear Ainsworth knows what male and female are, not only from this comment but also from her own biology research, and yet she prioritizes the sociopolitical efforts to redefine sex according to subjective identity over the reality of our sexed bodies.
Summary points
Sexes are ancient. Male and female are fundamental properties of human beings. They’re the ancient, 1.2-billion-year-old mechanisms by which we reproduce. And such mechanisms of evolution have created important sex differences across biological, psychological, and social levels.
The sex of individuals is important. It is often very important to know whether someone is male or female, and other times, it does not matter. Just asking someone whether they are male or female is not the right approach in all situations. Scientific, medical, legal, and social contexts all require us to know someone’s sex, sometimes for the person’s own health and safety and sometimes for the health and safety of others.
Sexes are not redefinable. There is no need to redefine the sexes of male and female to accept those who are atypical. In fact, those with sex development conditions and those who are trans can only exist because there are only two sexes, male and female. Thus, the irony becomes clear: Erasing male and female would mean erasing the existence of both such groups.
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Bibliography
1a. Parker, GA., et al. (1972). The origin and evolution of gamete dimorphism and the male-female phenomenon. Journal of Theoretical Biology, 36, 529-553.
1b. Kodric-Brown, A., Brown, J. (1987). Anisogamy, sexual selection, and the evolution and maintenance of sex. Evolutionary Ecology, 1, 95-105.
1c. Hoekstra, R. (1990). The evolution of male-female dimorphism: older than sex. Journal of Genetics, 69(1), 11-15.
1d. Charlesworth, B. (1994). The nature and origin of mating types. Evolutionary Genetics in Current Biology, 4(8).
1e. Czaran, T., Hoekstra. R. (2004). Evolution of sexual asymmetry. BMC Evolutionary Biology, 4(34).
1f. Lehtonen, J., Parker, G. (2014). Gamete competition, gamete limitation, and the evolution of two sexes. Molecular Human Reproduction, 20(12).
1g. Schärer, L. (2017). The varied ways of being male and female. Molecular Reproduction & Development, 84.
1h. Lehtonen, J. (2021). The legacy of Parker, Baker, and Smith 1972: Gamete competition, the evolution of anisogamy, and model robustness. Cells, 10(573).
2. Dumic, M., et al. (2008). Report of fertility in a woman with a predominantly 46,XY karyotype in a family with multiple disorders of sexual development. The Journal of Clinical Endocrinology and Metabolism, 93(1), 182-189.
3. Lehtonen, J., Parker, G. (2014). Gamete competition, gamete limitation, and the evolution of two sexes. Molecular Human Reproduction, 20(12).
4. Eggers, S., Sinclair, A. (2012). Mammalian sex determination: Insights from humans and mice. Chromosome Res, 20.
5. Lehtonen, J., Parker, G. (2014). Gamete competition, gamete limitation, and the evolution of two sexes. Molecular Human Reproduction, 20(12).
6. Kimball, J. (2020). Sex chromosomes. LibreText.org
7. Eggers, S., Sinclair, A. (2012). Mammalian sex determination: Insights from humans and mice. Chromosome Res, 20.
8. Kashimada, K., Koopman, P. (2010). Sry: the master switch in mammalian sex determination. Development, 137.
9. Kimball, J. (2020). Sex chromosomes. LibreText.org.
10. Eggers, S., Sinclair, A. (2012). Mammalian sex determination: Insights from humans and mice. Chromosome Res, 20.
11. Warr, N., et al. (2012). The molecular and cellular basis of gonadal sex reversal in mice and humans. WIREs Dev Bio, 1.
12. Lanciotti, L., et al. (2019). Different clinical presentations and management in complete androgen insensitivity syndrome (CAIS). International Journal of Environmental Research and Public Health, 16(7).
13. Wang, S., et al. (2009). Androgen receptor roles in spermatogenesis and fertility: Lessons from testicular cell-specific androgen receptor knockout mice. Endocrine Reviews, 30(2), 119-132.
14. Oakes, M., et al. (2008). Complete androgen insensitivity syndrome--a review. Journal of Pediatric and Adolescent Gynecology, 21(6).
15. Barros, B., et al. (2021). Complete androgen insensitivity syndrome and risk of gonadal malignancy: a systematic review. Annals of Pediatric Endocrinology & Metabolism, 26(1), 19-23.
16. Bachelot, A., et al. (2017). Management of endocrine disease: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: update on the management of adult patients and prenatal treatment. European Journal of Endocrinology, 176(4).
17. Colet-Ipulan, L. (2022). Sexual dimorphism through androgen signaling; from external genitalia to muscles. Frontiers in Endocrinology, 13.
18. Sherwani, A., et al. (2014). Hysterectomy in a male: A rare case report. International Journal of Surgery Case Reports, 5.
19. Chua, I., et al. (2022). Persistent Müllerian Duct Syndrome: understanding the challenges. Case Reports in Urology, 2022, 2643833.
20. Josso, N., et al. (2020). What does AMH tell us in pediatric disorders of sex development? Frontiers in Endocrinology, 11.
21. Thorpe, J., et al. (2020). Mosaicism in human health and disease. Annual Reviews in Genetics, 23(54), 487-510.
22. Shrivastava, S., et al. (2019). Microchimerism: a new concept. Journal of Oral and Maxillofacial Pathology, 23(2).
23. O’Donoghue, K. (2008). Fetal microchimerism and maternal health during and after pregnancy. Obstetric Medicine, 2008, 1.
