The Problem With Swaab

Sophia Siedlberg


Issue 25
Spring 2004

In 1995 Professor Dick Swaab announced to an indifferent world that the probable cause of transsexualism was perhaps linked to the relative sizes of the Anterior portion of the Bed Nucleus of the Stria Terminalis. Unfortunately a lot of political debate erupted around this and it is probable that a lot of good science was lost in the debate. The issue for Swaab was perhaps finding some proof of a condition from a neurological standpoint. The issue that most people latched on to was the notion that "Transsexuals cannot help being transsexual" (To quote the popular press at the time) what this revealed was a strange mindset that concentrated on the idea of biological essentialism, and the opposing mindset of social determinism. I looked at this, thinking that that aspect was basically irrelevant. Simply because Professor Swaab had probably unlocked some interesting clues about how cell differentiation and apoptosis seems to work, with respect to steroids.

It is well known that steroids have a very profound effect during our lifetimes. Puberty is perhaps the best known example where a small family of "sex" steroids affect many things from bone maturation to metabolism. But the idea that they may have an influence before birth seems to be little discussed. And when it is it seems to be to justify medical practices that are to say the least questionable if sex differentiation is involved.

The basic question was whether or not androgens influenced the "gender identity" of an individual in utero, specifically with respect to the BSTc which provided tentative evidence to suggest that this was indeed the case. I myself have little or no problem with this idea because as I say it provides clues about cell differentiation that can impact on other branches of medicine, most notably the role steroids may play in brain tumours. (More on that later)

So to the distracting arguments. The first argument was based on a misnomer. That androgens "masculinise" the BSTc. and as such this produces a "male brain sex". In truth the situation is quite different. The cluster of cells in question appear to grow to a particular size and then start to die off, settling at a cluster who size is determined by which steroids are present. It appears that androgens slow down the rate of cell death, and estrogens do the same but to a lesser extent. The appearance of steroids seems to regulate how much this cluster of cells reduces in size, rather than how large this cluster grows initially. That is actually very significant to someone who may have an interest in oncology. Here we have a ready made apoptosis inhibitor. Superficially the only conclusion I can draw from this is that ring A in a steroid has some probable influence on this. With the "feminising" steroids (estradiol and estrone) the carbon atoms are all double bonded. 2-3 4-5 and 19-1 in estrone, and 1-2, 3-4 and 5-19 in estradiol. With androgens you have either one double bond or none, and the cys/trans configuration of the hydrogens bound to the carbon atoms often seems significant as well. If there were experimental data to back up this idea the question would then of course be how the configuration of an A ring in a steroid nucleus (Cholesterol perhaps) would affect apoptosis? I mention this because such an idea is flatly contradicted by the current en vogue theory that in the absence of certain steroids (specifically dihydrotestosterone) has no effect on the reduction of the size of the BSTc from its initial mass. Considering that DHT is a classic example of the model I have just described, where the 5 carbon atom has a hydrogen atom in a trans configuration. Testosterone is bounded 4-5. and thus biologically less active.

According to my model it would be difficult to see how the BSTc would reduce less were DHT not present. Considering the role DHT plays with respect to tissues elsewhere in the body. We are really looking at androgen receptors and how they function. Do the binding domains of androgen receptors bind to various nucleotides inhibiting the production of signalling peptides or promoting the production of inhibitory peptides in certain nerve cells? If so, does the event that causes the binding domain to do this (the fitting round a certain type of steroid) really extrapolate into something different from the text book idea that DHT, when absent, does not slow down or inhibit apoptosis. It stands to reason that it would lock into certain androgen receptors, thus resulting in apoptosis inhibition, not what the gender psychologists would have you believe.

So what is the problem with Swaab? Well the problem is that Swaab has come up with some experimental data that may well prove interesting to an oncologist looking into the way apoptosis works in nerve cells. The "yuk" factor often associated with gender identity issues has bluntly obscured some very interesting possibilities. Who knows one day you may find people thanking transsexual people for being the clue to curing brain tumours. (But this is optimistic thinking in scientific terms and not "social" terms).

So what is the issue I have here? Well as with any mechanism of "sex differentiation" the process of understanding something as detailed as the binding domains on androgen receptors or the configuration of the A ring in any given steroid seems to become lost in the midst of "debate". McGinley and Diamond maintain that people with 5alpha reductase deficiency all identify as male, Diamond even cites the 5alpha model (textbook as defined by McGinley) as being the root of a masculine identity. But it does not add up in my mind - especially when you consider he quotes Swaab as the author of the textbook female brain. There is a plain contradiction here. Swaab's model suggests what I have written here. McGinley's model suggests the exact opposite. They cannot both be right. I am not saying I am correct, but I am saying that given my understanding of steroids, receptors and so on, the two ideas don't match. Are we really seeing theory pandering to gender politics here? And in doing so missing out on very interesting possibilities with respect to other areas of research?

So the problem with Swaab is that what he has published contradicts accepted norms. Looking at his data and trying to work out what may be going on leads to ideas that contradict accepted notions about sex differentiation, McGinley being a classic example. Where do we go from here, I ask? Well I want to look at the root of all this NAIP or Neural Apoptosis Inhibitory Protein, which prevents the process of apoptosis by preventing the activation of Caspase 3 with Caspase 9. Is the production of this protein affected by the presence of binding domains on the AR binding to a region of the gene that codes for NAIP? (an on/off switch if you like) Can the AR binding domain be one of a number of factors that causes the NAIP gene to express? If so, is it reasonable to assume that it may be worth looking again at how steroids interact with receptors? Two parts of a pathway that need to be looked into. Personally I would say this was quite important and should be looked into, not as a piece of research to identify the root cause of transsexualism alone, but as part of a wider piece of research to look into how neural apoptosis works in conjunction with such unlikely entities as androgen receptors. Because somewhere in all this I find myself asking why, with the still slow progress of research into brain tumours, especially brain tumours that are secondary to steroid dependant tumours elsewhere in the body. This is not being looked into, and it is not being looked into because of the prejudice towards transsexual people and the condition they report having. It is all well and good to say "Ah but we have brain sex" and to try to provide a model as an example, but without looking closely at this model, specifically Swaab's and looking at what may be happening as a continuation of Swaab's research. The "problematic" nature of what he has found, may well result in a lower survival rate for brain tumours in years to come.

Conclusion and clarifications.

The basic proposition of the model presented here is that the habit ARs have of binding to bits of DNA in order to promote or inhibit the coding of certain peptides. Either other steroid (estrogen receptors) receptor binding domains bind to prevent the production of NAIP itself, which would create a situation where estrogens would increase the process of apoptosis in target cells. (I feel this may be unlikely) or that androgen receptors bind to some on/off switch, presumably a signalling peptide coding region that would then vary the rate at which NAIP is produced. It seems that it may be more likely, given that the actual BSTc sizes vary greatly from individual to individual. Swaab did report overlaps in BSTc sizes relative to gender. Also with respect to oncology, it is known that a number of mutations in the androgen receptor gene affect the appearance of steroid (androgen) dependant tumours, of which brain tumours are often secondary. Testicular cancer is perhaps the most interesting in this respect.

Either way, while the model I am presenting here is purely hypothetical, and based mainly on the work of Swaab, I feel that some experimental work may well produce interesting results for oncologists looking into the relationship between steroid dependant tumours and numerous brain tumours.

Other articles by Sophia Siedlberg:

Web page copyright GENDYS Network. Text copyright of the author. 19.08.03 Last amended 22.08.03