By
Sophia Siedlberg,
Bio-informatics Developer in the United Kingdom and supporter of the AIS Support
Group Australia.
As
someone who is intersex the worst career move I ever made in terms of my self
esteem, was to become a "Bio-informatics" developer. This is
because I write software that deals mainly with proteins and genetic analysis, a
branch of science that often is seen to affect the way I am seen by society at
large.
The media
often make proclamations about a "Gene for this" and a "Gene for
that" and numerous commentators appear in the media discussing "The
Human Genome project" they initially thought would categorise every human
being on the planet according to a set of simplistic criteria. Problem is,
there is a paradox here. You need a very large genome of some 100,000
genes all expressing singularly for a specific purpose, to set up such a
simplistic model of the given gene pool. In plain language, you need to
have each and every gene doing one single thing. For example, when you
need to have a gene for "Gayness" you say "Ah we have a single
gene that makes someone gay". This example of single gene paradigm
was espoused a few years ago by one Professor Dean Haymer who isolated a
fragment on the X chromosome that seemed to appear every time the owners of said
Gene on chromosome X said they were gay. Well in the great scheme of
things this gene was given the name of "Xq 28". Now anyone who
knows genetics will tell you that this gene has yet to be named. "Xq"
only defines the location of this gene, it is not any official name referring to
its purpose, function, resulting proteins from the coding exons etc. This
may be in part due to the fact that the Jury will still be out on this for some
time.
This is
where single genes cease to become paradigm. What does this gene actually
do, what peptides, proteins, enzymes etc does it code for? What function
do these coded proteins etc actually do to make someone gay? The reality
is, of course, far more complex. Whatever the gene codes for will interact
with something else, sometimes whatever another gene's exons code for.
This is a type of polygenic expression as opposed to the single gene concept of
"monogenic" expression. The smaller the number of genes found in
a genome, the higher the probability of genes interacting with each other rather
than them simply expressing directly as a single gene. So when the human
genome project announced (with some disappointment) that there were only 33,000
genes, you can imagine the bewilderment. "It is more complex that
we thought!"
The often
quoted paradigm about chromosomes is: "XX equals a girl, whatever you say,
even if "she" is born
with a penis, has a six pack, looks like Arnold Schwartzenegger, and says that
"she" is a regular guy. Those XX chromosomes say that
really, deep down she is a woman." Or
"XY equals a boy, whatever you say even if "he" is born
with a vagina, looks like a supermodel and has all the attributes of a woman she
is secretly a man"
The term
often used is "true gender" or "genetic sex" by most
commentators. Now this is all built around two observations, first that
most people born with XX chromosomes are "female" and most people born
with XY chromosomes are "male". But as anyone with any
understanding will tell you, this is not always so. Secondly we are
given a single gene justification for all this, in the form of
"SRY", a gene on the Y chromosome. Now yes it does
produce a protein that differentiates gonadal tissue into testicular tissue
(Called TDF), but with a mere 33,000 genes and the demonstrable complexity of
"sex determination" the monogenic SRY concept does not add up.
This is
where many of the more unimaginative come to a dead end. They are so stuck
with "XX/XY paradigms" that when the obvious, "Polygenic
expression" becomes apparent it causes a disconcerting need for a paradigm
shift.
The
reality is more complex. With AIS alone there are numerous categories and
they can be as a result of many different AR (androgen receptor) mutations.
These mutations can be deletions, frame shifts, substitutions, mis-sense
mutations and so on. It can happen in one gene and cause a very profound
effect, but you can have something like 40 or so types of mutation resulting in
the same phenotype (Body type). At the same time you could have one type
of mutation resulting in many different phenotypes. This is because, while
you can pinpoint a single gene, the expression of that gene causes a cascade of
consequences rather than just one particular mutation equals one particular
phenotype because other genes interact or by expression vary the outcome in many
different ways. The more alleles there are of a given gene the more
complex it gets within the gene pool. In plain terms we are all
individuals!
Given that
I can start quoting examples of genes that are not in X or Y but the autosomes,
that may contain AR coding exons besides the AR gene itself, the whole edifice
of the "XX/XY paradigm"
starts to crumble. In sheer confusion many in the field run around
collecting blood samples from any hapless IS person they can get their hands on
and then run to the lab. After a little spin of the centrifuge, you will
find them with their Li-cor machines, Electrophoresis boxes or micro-arrays
desperately trying to simplify the picture into "Boy or Girl", and
then you will find them pouring over their inheritance charts.
They get
to find the exons in the "offending genes", and the mutation and then
there is the challenge of the resulting peptides. Mention Chou Fasman equations
and watch some of them puff up and
say "this determines the shape of a peptide, by assigning specific values
to the amino acid residues". When you say something really awful like
"lets think of Prions, you know CJD, Mad cow disease, how come you can get
the same sequence but one becomes Beta sheets and the other becomes Alpha
helices?", and we are into proteomics when pointing out that Chou Fasman
equations have limits. OK Prions (the cause of CJD) are a different
matter, but a good illustration. The proteins behave in many strange ways,
take many strange shapes and, as such, interact in many strange ways and there
are many reasons for this.
It takes a
protein scientist to look at this with an intuitive eye, good protocol as well
as some damn good lab facilities. They need to crystallise these proteins, throw
X-rays at them, and use specialised software (Plug) to assess the results.
The problem is that the real complexity leaves people asking the fundamental
questions again, sometimes (I have to be honest), those fundamental questions
are not re-appraised.
Now there
is a maxim that often holds true, it goes like this: The more complex a
system, the less predictably it will behave. For example many people
who buy a new computer, tend to think that there is a set way to deal with
problems that may arise. So what sometimes happens is that they will buy a
patch or a utility and install it, only to find that the computer does not do as
it is supposed to after the installation, often to the despair of the owner.
This is because a new layer of complexity has been added.
Quite
often there is a simpler solution, if it works, why potentially make it worse.
Another example would be to dismantle a washing machine in order to put the
clothes into it. Just because someone says you cannot use the door (a
paradigm lets say) and then expect the washing machine to work once you have
re-assembled it with the clothes in situ. Well, recently a gene on chromosome
one, the aptly named "WNT-4", has become a potential symbol of this
kind of systemic "fix it at your peril" paradox.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Gene
Duplicate Causes Sexual Ambiguity
In
one out of every 3,000 births, the physician cannot tell the new parents what
some have waited to hear But the results of a study described in the May issue
of the American Journal of Human Genetics may offer new hope to parents whose
infants are born sexually ambiguous. According to the report, researchers have
determined that a second copy of a sex determination gene known as WNT-4 can
change an embryo from male to female, which often results in ambiguous
genitalia. The finding could help doctors more accurately and quickly identify
an externally ambiguous baby's gender.
Geneticist
Eric Vilain of the University of California at Los Angeles and his colleagues
identified WNT-4 as one of several genes that determine sex.
Whereas
most genetic defects stem from the absence or mutation of a gene, genital
defects arise when WNT-4 appears twice on the chromosome. WNT-4, it seems,
"influences the sex determination pathway at each step of the way,"
Vilain notes. "We discovered that when the amount of the gene fluctuates
even slightly at any stage in the genetic blueprint, it changes the embryo from
male to female."
The
WNT-4 study results will enable researchers to use genetic testing to help
identify the causes of genital ambiguity. Moreover, scientists might one day
even be able to treat a defective embryo in utero. "Our findings suggest
that clinicians could identify the WNT-4 duplication prenatally," Vilain
remarks. "If this proves true, in the future we may be able to correct the
defect in the womb and restore the embryo to its original male status. This may
repair the genital malformations before the child is born."
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Notice
also how the emphasis is made about parents
"may offer new hope to parents
whose infants are born sexually ambiguous.",
as if stating that the parents are the ones who are afflicted, the child is
the passive bystander or property that causes embarrassment. What I am
saying is really simple; such theorising about future medical approaches is both
deeply questionable from an ethical standpoint, as well as indicative of that
persistent near genocidal hatred of intersex people and shows a sense of
difficulty with polygenic expression.
Biologically
there are a number of questions I have. It has become obvious from the
findings of Professor Vilain that we are looking at polygenic expression here.
The question here is; why does it seem so important to say that even in
recognising polygenic components to sex determination that run through the
autosomes, if the foetus has a "Y" chromosome in the 23rd pair it must
be made into a boy, or it is established as being male?
This is a contradiction. There is a pathway of autosomal entities
involved, the complexity of which is not understood and to satisfy the need to
say "Y=BOY" or "X=GIRL" the solution is to risk altering
numerous coding exons within a copied gene (in this case delete them
altogether), to "Fit" the fact that chromosome Y or X
is present. No regard is given to the potential health risks that may
be involved. The possibility of compromising the individuals health is
far greater by taking the "Autosomes will obey the sex determinants"
approach, rather than just accepting the fact that "Y does not always =
Boy" and "X does not always = Girl".
The main
reason for objections to a notion of "designer babies" has more to do
with the not so clear model of polygenic expression and the very probable
polymorphisms that may result. You can re-engineer
a gene in some area but what that will mean in terms of other genes interacting
with it will for the most part remain unclear. This study has unintentionally
demonstrated this quite starkly. Current attempts at using somatic gene therapy
have shown this to be the case to some extent, with numerous examples of the end
result not being what was expected. There is little or no concept of risk
management in this suggestion that a pre natal treatment for intersexuality can
be implemented. Like earlier methods of "treating"
intersexuality, there is a danger that such intervention will do more harm than
good.
Dr Money
for example claimed that "gender identity" was psychological and a
product of upbringing, this was proven to be wrong, the reason is most likely
because the people in his care were not even consulted. The risk of course
is that of having been forced to live as someone else and in the case of
surgical intervention, to face the risks of later complications. The problem is
that the cause and effect model of treating intersex people does not account for
the fact that there are so many genes containing coding exons that can alter the
"sex" of the foetus. This in itself should be a reason to stop
and think before trying to dictate who is what and who will be what.
So in
brief the very suggestion (which suggestion?) shows an obvious lack of
understanding about the dynamics of polygenic expression. There is
discussion here not about a "single gene" disorder, but
"Polygenic gene" correction. It is difficult simply trying to
treat a single gene with a single outcome, yet alone forcing a gene to interact
in context with other genes. In this case, more frighteningly, to remove a
second copy of the gene in question altogether. So this brings me back to
my little pun about the name of this gene, WNT-4. The irony here is that the
name of this gene reminds me of a certain computer operating system that behaves
just like a polygenic contextualisation as a complex system.
See the not so useful patch or utility as the "chromosomal
material" (suggested approach) and see the host operating system as being
the polygenic array. Added complexity - Q.E.D.
On an
ethical level, are intersex people regarded so poorly by society that society
would sanction such uncertain uses of genetic manipulation,
when somatic gene therapy on single gene conditions has yet to become viable?
I really wonder about society itself and its attitude towards those it considers
unable to fit the two sex system when discussing a very theoretical assumption
that you could patch up the genome at such a complex point.
The
language is very puzzling to me as well. I have already discussed in some
depth how "Male" and "Female" foetus cannot be regarded as a
valid term, because of polygenic expressions of the type WNT-4 appears to be.
What is really meant by saying that we have a "Feminised male foetus"?
It should be quite evident that to say "XX/XY " is not the overriding
marker of gender and sex because the evidence shows clearly the contrary,
resulting in a contradiction of terms. What makes this research extremely
difficult for me to understand is
the fact that the people conducting the research are somehow prepared to suggest
taking the hardest route possible, a route that is the most convoluted, in order
to establish the most simplistic and flawed
paradigms. As I said earlier, would you dismantle a washing machine
in order to put the clothes into it. Just because someone says you cannot
use the door and then expect the washing machine to work once you have
re-assembled it with the clothes in situ? No! So where is the logic
behind this research if it is not simply another example of the need to believe
in the increasingly untenable? The reality here is simple XX does not
equal a girl and XY does not equal a boy. The genes involved in the sex
determinants evidently are part of a broader picture and to try to make the
picture fit in such a limited way is no different from the surgical mutilation
of intersex children, based on the flawed assumptions laid down by society and
not genuine science.
And then I
have to ask myself what this means: "The
finding could help doctors more accurately and quickly identify an externally
ambiguous baby's gender." If
by "gender" they mean "how they themselves will identify"
then they are fully missing the point I make. They cannot even get to
grips with the most basic aspects of human behaviour with respect to genetic
causality, yet alone self identity. If they don't mean "self
identity" when saying "gender" then they really need to qualify
the remark, because it is very vague and meaningless in that context.
The bottom
line is this. There is no such thing as an absolutely "Genetic" male
or "Genetic" female in much the same way as there is no absolute
"Male" or "Female" gender identity, just a spectrum of
expressions. There is no such thing as a "true gender" just a
bias. The whole edifice of trying to make an intersex child
"fit" into some more absolute image of one or the other sex is to put
it bluntly, rank stupidity. This is why I find my self esteem undermined
when someone working in the field hits me with "Oh I need to find a way of
using computer models to prove you don't exist." But then if I don't
exist, because of my intersex birthright, how can I have a brain to comprehend
what the genie has in terms of specification, a brain to code the software, a
brain and hands to actually type the code for the software, and arms and legs in
order to physically distribute this work.
So to conclude I am confused by the ideas put foreword by Eric Vilain. I cannot see the way foreword as being as simple as this, I also do not find the idea in itself to be very ethical either. I think my real concern here is that the general notion that intersex people are a "social emergency" or "a problem". It undermines me as someone who works with genetics and proteomics as a bio-informatics developer and it also fails to match up to the evident complexity of what we are discussing here. I only hope as time passes social conformity of the sort prescribed here becomes less of a priority and the real issues of the individuals health and well being become more important. To blindly follow a path without considering the consequences will lead to problems for future generations to deal with.
Sophia Siedlberg.
with
questions or comments about this web site.