Murdoch
Children’s Research Institute Sex Study
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.
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