GENETIC ISSUES

"Genetic engineering with its pre-determination disturbs me. It robs humanity of the unknown factor that makes life worth living." - Jean Luc-Picard, Captain USS Enterprise NCC1701-D

Inquiry into the Protection of Human Genetic Information

The Australian Law Reform Commission (ALRC) conducted an inquiry on behalf of the Commonwealth regarding the protection and use of human genetic information. As a group concerned with genetic variations, this has many important implications for people living with intersex conditions for current and future generations.

The AISSG Australia has made two submissions on February 2002 and January 2003.

Murdoch Children's Research Institute Sex Study

By Assoc. Professor Andrew Sinclair

In this article I would like to discuss my role in the Murdoch Children's Research Institute (MCRI) Sex Study and address the issues surrounding my work that were raised at the Brisbane national meeting. The aim of the MCRI Sex Study research program is to examine differences in sexual development by taking a comprehensive approach on: the genetics, clinical management, ethics and education. My role involves understanding the molecular genetic basis for testis and ovary development. At this point I should provide some background to explain why I am doing this work.

I have been working in the field of molecular genetics of sex since my Doctoral studies in 1988. My interest is in "Development", specifically, questions around how we develop such complexity from the fusion of two cells at conception. I have chosen to analyse the development of one system and have focussed on understanding how the testis and ovary develop in the embryo. Why choose this system? Why not choose another organ? A common problem is that most organs are vital for life. Any differences in the genes that code for these organs will not show subtle effects (that point to the true function of the gene) but lead to fatal organ failure. Differences in the genes that code for gonad development are not lethal but manifest as changes to gonad structure and function. This in turn points to the precise function of those genes. By contrast, in an organ such as the heart small differences in the genes controlling heart development may result in heart failure. This would lead to foetal death and so nothing could be learned of gene function.

Primarily I want to know how genes and their products cause different cell types to form the enormous complexity inherent in gonad structure and function. This in turn provides fundamental insights into the development of many other organs. This is because many of the key genes required for organ development are the same. We are one of six major groups around the world working on sex determination. After 14 years of studying the molecular genetics underlying the development of the testis and ovary I believe we have learnt a great deal. My early work led to the isolation of the key gene on the Y chromosome that is required for testis development. Since then a range of other genes required for testis and ovary development have been identified. We have shown that one important gene required for testis development also plays a crucial role in the bone development. Other testis genes are also involved with kidney function. This has reinforced the view that many of the same genes are re-deployed to build different systems and organs.

In the course of this research we have analysed some of these testis-determining genes in DNA from intersex patients. We found that in some patients the testis genes have a minor difference in their genetic code. This may result in a gonad with a slightly different structure that may produce more or less of a particular hormone, which may in turn lead, to different genitalia. Analysis of DNA from such patients is enormously instructive because it tells us about the subtle function of these genes. It has also taught me that there is a great spectrum gonad structure and function in the population. The more we study genes in patient groups and the population at large the more we realise that such differences are not "abnormal mutations" but rather reflect the great diversity and variation that makes up the human species. The term intersex covers an enormously wide spread of conditions all with very different causes. I think our research can offer a more complete understanding of such gonadal/genital differences. Hopefully this will help intersex individuals (and others) to see themselves as just another manifestation of human sexual diversity.

Issues raised at the Brisbane national meeting

Information from genetic research could be used for pre-natal screening with the aim of aborting children with intersex conditions.

The aim of our research is to understand the genetic basis of development at its most fundamental level. Our pre-existing study into the genes controlling gonad development has been incorporated into the more recent Sex Study. We have no intention of using these genes to produce pre-natal intersex tests. The use or otherwise of such genes in a democratic society should ultimately be determined by informed public debate. This issue is relevant to a whole range of genes that have been discovered as part of the human genome project. My hope is that information gained from our research can be used as a solid factual base from which to change societal attitudes.

Information from genetic research could be used for "gene-therapy" to eliminate intersex conditions.

We have no intention of using our research findings for gene-therapy to eliminate intersex conditions. In my view such "therapy" is not something that should be considered for intersex. Gene therapy in this scenario is unlikely to be feasible, as it would have to be administered to the foetus in utero prior to the testis or ovary gene having been "turned on." The case for gene-therapy and its efficacy are often greatly exaggerated. Gene therapy is likely to be used for only the most severe and life threatening conditions.

Information from genetic research is not sufficiently safeguarded and once information is available, it is too late to do anything about it if used for purposes not originally intended.

Our research program at MCRI has met the extremely strict requirements of our human ethics committee. Specific provision for safeguarding of genetic information is in place. Data obtained during the study will be stored in a form that is identified only by a code number, rather than by a patient's name. The code will be securely kept in another place that will be accessible only to the Principal Investigators.

Why isn't research being directed to such things as establishing the reason for the high incidence of low mineral bone density in those with AIS?

Prof. Garry Warne and Prof. Jeffery Zajac have already studied bone mineral density (BMD) in some of our AIS patients and would like to extend the study in a larger group. Once we have begun the main study, it will be relatively easy to carry out other side studies and we have plans to examine this important measure of health. These additional studies can be undertaken by making supplementary applications to the human ethics committee. We would also need to identify a source of research funding for the mineral density scans but this should not present any difficulty.

The Sexes: New Insights into the X and Y Chromosomes

The distance between Mars and Venus might be closer than previously thought.

By Bob Beale in The Scientist 15[15]:18, Jul. 23, 2001 (Link on accessmylibrary.com)

The cry of "It's a boy" or "It's a girl" marks the newborn child's first and most basic label of personal identity. But researchers' understanding of sex is undergoing profound and surprising changes due to new insights gained from sociology, biology, and medicine. The differences between females and males, once believed black and white--or pink and blue--now appear like a blurred rainbow of confusion. Researchers are learning, for example, that the Y chromosome has degenerated over the centuries. They have found that, in mice, some genes involved in early stages of sperm production are on the female X chromosome; and they have identified the gene that can produce ambiguous genitalia.

Genetic studies are revealing that men and women are more similar than distinct. So far, of the approximately 31,000 genes in the human genome, men and women differ only in the two sex chromosomes, X and Y, and only a few dozen genes seem to be involved. Moreover, it's now known that the Y has only about 30 genes and many of those are involved in basic housekeeping duties or in regulating sperm production. The X has hundreds of genes with a vast array of roles.

Strong evidence exists that these two chromosomes were once a matching pair of Xs, says Jennifer Graves, a genetics researcher at La Trobe University, in Australia. According to Graves, it's unclear why the male sex chromosome, the Y, shrunk and shed most of its genes over time. Humans are not alone in this. The Y chromosome's degeneration is well documented in fruit flies and "is clearly an ongoing process in all animals," says Sherman Silber, a medical doctor and director of the Infertility Center of St Louis.1

Past assumptions regarding these sex chromosomes are being challenged: It's recently been discovered that in mice, nearly half of all genes involved in the earliest stages of sperm production are found on the X. "Scientists and non-scientists alike are comfortable thinking about the Y chromosome as a specialist in male characteristics," says David Page, who headed the discovery team at the Whitehead Institute for Biomedical Research in Boston.2 "By default, we've traditionally thought of the X chromosome as sexually neutral or as a specialist in female characteristics," Page says. "Our findings indicate that the X chromosome has a specialty in sperm production, much like the Y chromosome does."

Sex-Determining Genes

Detailed molecular and embryological studies are revealing how genes determine the anatomical sex of a fetus and how that process can and does go awry. Andrew Sinclair, who now heads the Centre for Hormone Research, University of Melbourne, was part of the British-based team led by Peter Goodfellow, of the Imperial Cancer Research Fund, which in 1990 discovered a crucial gene, known as SRY.3 It usually occurs only on the male Y chromosome. Using this discovery, researchers at Britain's National Institute for Medical Research then showed that a fertilized female mouse egg will become male when injected with SRY. The animal in question, named Randy, was the first sex-reversed mouse ever produced in this way, Sinclair says. The testes were small but Randy otherwise grew up male in every discernible way, despite being conceived as a genetic female. Placed in a cage with some females, Randy behaved in a typically male-mouse way, mating up to six times a night. "He thought he was male, they thought he was male, and we thought that was pretty good evidence," Sinclair says. "It tells you that SRY is the only gene you need on the Y chromosome to develop testes and become male."

But other genes complicate the process of sex determination. One known as DAX1, for example, is thought to act as an anti-testis gene, promoting ovary development. Another, called SOX9, combines with SRY to promote the formation of testicular cells in a male embryo. A third gene known as WNT4 and found on chromosome 1, seems to prevent the development of Leydig cells in male testes.4 Researchers led by Eric Vilain, assistant professor of human genetics, University of California, Los Angeles, recently found that when WNT4 occurs twice it can convert an embryo from male to female, often resulting in ambiguous genitalia.5

Neutral Starting Position

It is often argued that being female is the default state for mammals; that an embryo will develop in a female way unless male genes impose themselves on the process. It now seems just as possible, however, that the default state is merely a sexless one, a case of dual potential. In the first six weeks after conception, a human embryo develops a simple gonad that is neither a testis nor an ovary, but more of a neutral sex bud that can bloom either way. The bud has two parts, the medulla and cortex. At about seven weeks, when the fetus is thumbnail size, the SRY gene, if it is present, starts to work its magic. It switches on and the cells in the medulla start to multiply and form into a testis, while the cells in the cortex regress and virtually disappear.
Every significant distinction between men and women apparently stems from that event. As Graves puts it: "Of all the differences between male and female mammals, the primary one seems to be the development of the testis in males. Early in development the mammalian embryo is ready for anything. Male and female embryos are morphologically indistinguishable ... and the embryo is equipped with both male and female internal ducting." The development of the testis triggers a cascade of hormone-controlled changes, so once this decision--testis or no testis--has been taken, the sex of the embryo is determined. Within a week the new testes soon start producing their lifelong supply of testosterone, which floods the embryo and kicks off the development of typical masculine physical traits. If no SRY gene is present, the embryonic gonad waits until the 13th week of gestation to commit itself to femaleness. The medulla shrinks away and the cortex develops into an ovary, which starts to produce estrogen and feminizes the rest of the body.

The differentiation process in the womb can be affected, however, by genetic problems, infections, or exposure to toxins, drugs, or maternal hormones. In that context, it's remarkable to note that SRY's discovery was made possible with the help of French scientists who identified four unusual men who had sought treatment for infertility, Sinclair says. Chromosome tests revealed that they were in fact genetic females, with an XX female sex-chromosome pattern. Yet all four were anatomically male and had testes. Further studies showed that they had a small fragment of Y chromosome containing the SRY gene, tacked onto one of their X chromosomes. It was just a tiny glitch, enough to reverse their sexual anatomy but not endow them with other male genes to enable their testes to make sperm.

Many other such variants are now being discovered, along with true hermaphrodites and pseudo-hermaphrodites. There are people with missing sex chromosomes, extra sex chromosomes, or tiny genetic fragments tacked onto or missing from chromosomes that seem to have nothing to do with sex determination.

Delving into the very fundamentals of sexual genetics and biochemistry and making personal contact with people whose sex and gender are ambiguous has made Sinclair see the whole issue in a fresh light. "I think humans like things to be ordered, and they get bothered about gray areas and when things become less clear-cut," he says. "But these days I don't think so much in black and white about male and female. Now I think of it all as being on a spectrum."

Bob Beale is a freelance writer in Sydney, Australia.

1. S. Silber, "The disappearing male," Proceedings of the 11th World Congress in In Vitro Fertilisation and Human Reproductive Genetics, May 1999.

2. J.P. Wang et al., "An abundance of X-linked genes expressed in spermatogonia," Nature Genetics, 27[4]:422-6, 2001.

3. A. Sinclair et al., "A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif," Nature, 346:240-44, 1990.

4. "Making Babies," New Scientist, 2290:36-7, May 12, 2001.

5. B.K. Jordan et al., "Up-regulation of WNT-4 signalling and dosage-sensitive sex reversal in humans," American Journal of Human Genetics, 68[5]: 1102-9, 2001.

Prenatal Diagnostic Testing in Victoria 1983 - 1998

By Tony Briffa (This article appeared in dAISy March 2001.)

In light of the recent discussions on prenatal genetic testing for intersex conditions, I have obtained and reviewed the publication "Birth Defects in Victoria 1983-1998" Perinatal Data Collection Unit, Victorian Government Department of Human Services, Melbourne, August 2000.

Note: I do not support the use of words like "defect" or "abnormal" when it comes to intersex conditions like AIS, CAH, Turners and Klinefelters. As I am reporting on the facts contained in this publication, I will use their terminology.

Some statistics in this publication include:

Birth Defects 1983 - 1998

- 213 Turner

- 77 Klinefelter

- 189 Other Sex Chromosomes

Terminations before 20 weeks gestation, 1989 - 1998

- 98 Turner

- 28 Klinefelter

- 39 Conditions due to other sex chromosome anomalies

I have many friends with Turners and 47XXY (otherwise known as Klinefelter Syndrome) and I am appalled that terminations are recommend or that they are even classified having a "major defect". These friends include academics, a retired politician and schoolteacher (who was knighted for his service to the Parliament), Engineers etc. I am concerned that women who are told they have a child with in intersex condition are being told that their child will have major abnormalities without even contacting the relevant support groups and meeting some adults with the same condition that their child has.

There are still many doctors who refuse to let teenage and adult patients know about the presence of support groups, just as there are doctors who withhold the full truth about a child's intersex condition from their parents. Given that this is the case, what are the chances that some doctors will be upfront and completely honest with a woman who is pregnant and who may consider terminating a child with this "major defect"? I know not all doctors would recommend this, that didn't stop the termination of 165 children with intersex conditions in a ten year period in the state of Victoria alone.

There recently has been has been talk of screening for AIS along with other "major defects" such as Down Syndrome, Cystic Fibrosis, and Spina Bifida. I am personally against this, and think of all the wonderful friends I have with AIS all over the world and how much they have added to my life and that of all their friends and families.

In case of prenatal genetic testing I have to agree with Garry Warne's comments of dAISy September 2000 "It is a mistake to focus too much on the medical aspects of AIS." (Dr Warne is also personally opposed to genetic testing for the termination of intersex infants). I believe that screening for AIS will lead to the further medicalisation of AIS and those of us with it without any benefit to our lives, while culling future generations of our special AIS siblings.

I would rather see a focus on improving our quality of life with an emphasis on counselling, support, research into osteoporosis, fertility and hormone therapy, truth disclosure, improved surgical techniques for adults wanting vaginoplasties or phalloplasties, increased knowledge and emphasis on non-surgical dilatation, legal status of people who identify as intersex (i.e. not exclusively male or female), public education programs on AIS and our issues, etc.

UCLA geneticists identify cause of "malformed" genitalia, finding will improve sex assignments in "ambiguous" newborns

UCLA researchers have determined that a second copy of a human sex gene can convert an embryo from male to female, often resulting in ambiguous genitalia. Reported in the May edition of the American Journal of Human Genetics, the findings offer new hope for parents whose babies are born with this condition - as well as valuable information to help physicians more accurately and quickly diagnose the newborn's gender.

"Genital malformations are an unspoken yet frequent public health problem," said Dr. Eric Vilain, UCLA assistant professor of human genetics and principal investigator of the study. "Parents don't speak of it because they fear others will consider their children taboo or shameful."

"Our discovery offers insight into the genetic pathway of sex determination - what makes a man male and a woman female," added Vilain, a pediatrician who counsels parents whose children are born with genital malformations.

Mild cases of malformed genitalia - such as undescended testes or an enlarged clitoris - occur in one percent of all births, affecting 3 million people and their families. More severe cases - in which infants are born with such sexually ambiguous genitals that obstetricians cannot inform the parents whether they had a boy or girl - occur in one out of 3,000 births.

Vilain and his team pinpointed WNT-4, a signaling gene on chromosome 1, as one of a handful of known genes responsible for human sex determination. Unlike classic genetic defects that result from the absence or mutation of a gene, genital malformations occur when WNT-4 appears twice on the chromosome.

"These findings suggest that WNT-4 influences the sex determination pathway at each step of the way," Vilain said. "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 UCLA team's findings will enable physicians to use molecular testing to identify the genetic causes of sexually ambiguous genitalia in newborns. In turn, this tool will improve diagnosis for sex assignment.

"WNT-4 offers another diagnostic clue that explains why certain cases of sexual development go awry," Vilain said. "Firm diagnosis through genetic testing will equip physicians with the information they need to help parents make important medical choices early in their child's life."

Vilain's laboratory next plans to explore whether scientists can reduce the chromosomal dose of WNT-4 in the embryo of pregnant women whose first child possessed malformed or ambiguous genitalia.

"Our findings suggest that clinicians could identify the WNT-4 duplication prenatally," Vilain said. "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."

Following a private discussion on this article, Tony responded:

I'm glad that Eric Vilain is on NATFI, but I feel he has much to learn from the various intersex groups and our representatives. Without wanting to sound overly unfair, I think he first needs to understand the concept of gender, and that looking completely male or female does not make someone identify in that gender. We have seen this time and time again with both intersex and transsexual people.

Vilain is quoted as saying "Our discovery offers insight into the genetic pathway of sex determination - what makes a man male and a woman female". This is incorrect. What makes a man male or a woman female is the individual's brain and their self-identified gender. The way the body looks has nothing to do with it.

"These findings suggest that WNT-4 influences the sex determination pathway at each step of the way," Vilain said. "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." This part is mainly correct,
but what he means is that the amount the gene fluctuates changes the embryo from looking phenotypically male (or along male lines) to phenotypically female (or along female lines).

"WNT-4 offers another diagnostic clue that explains why certain cases of sexual development go awry," Vilain said. "Firm diagnosis through genetic testing will equip physicians with the information they need to help parents make important medical choices early in their child's life." Presumably he is saying that genetic testing will then enable physicians to surgically and hormonally reinforce the gender of assignment more confidently. I think this is dangerous. Very dangerous. Why not settle for simply raising the child as either male or female (without surgery) but leaving the right to self identify and body integrity to the individual? I think most children know by the time they are 12 if they want to develop as a male or a female. I am yet to see anything that suggests that genetics can ALWAYS predict the gender a person identifies. Given this, why should there be such a rush in surgically assigning gender?

Vilain's laboratory next plans to explore whether scientists can reduce the chromosomal dose of WNT-4 in the embryo of pregnant women whose first child possessed malformed or ambiguous genitalia. "Our findings suggest that clinicians could identify the WNT-4 duplication prenatally," Vilain said.

"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." I find this highly offensive. Many intersex people do not consider themselves defective. I certainly don't. If anything was defective it was the medical treatment I received. The treatment Vilain is hoping to create is vile. It is blatant gendercide. This so called treatment would have everyone with AIS born with completely "male" genitals, with nothing to guarantee the self-identified gender of these individuals. Whilst this outcome would be of benefit in my particular case as I am male, I am gravely concerned for the future generations of people with AIS as most identify as female.

I hope that NATFI listens to the intersex community about this very important issue. After all, intersex people are the true experts in living with intersex conditions.

I - like most in the intersex community and in line with the policies of the AIS Support Group Australia - would love to see the focus on research into intersex conditions shift into:

- research into hormone therapy (both testosterone and oestrogen),

- surgical techniques for intersex adults including vaginoplasty and phalloplasty,

- non-surgical dilatation,

- timing of gonadectomies,

- bone mineral density,

- fertility etc.

"The Gender Genital Gene Genie"

An article in response to genetic research conducted Eric Vilain at the UCLA. Written 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.

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