Gender-Specific Medicine and the Genome: A Complex and Evolving Tale. Marianne J. Legato, M.D., F.A.C.P. Professor of Clinical Medicine, Columbia University Director, Partnership for Gender-Specific Medicine at Columbia Adjunct Professor of Medicine, Johns Hopkins.
Gender-Specific Medicine and the Genome:A Complex and Evolving Tale
Marianne J. Legato, M.D., F.A.C.P.
Professor of Clinical Medicine, Columbia University
Director, Partnership for Gender-Specific Medicine at Columbia
Adjunct Professor of Medicine, Johns Hopkins
The past twenty years have witnessed
a profound series of changes in our approach
to and our achievements in biomedical investigation.
As a result, we have a radically new view
of normal human biology and the
pathophysiology of disease and indeed,
of the nature of life itself.
Instead of “what are the differences
between male and female?”,
many scientists are asking: “What
does it mean to be human?”
“What is normal depends on who is being compared to whom,
that many diseases have social and environmental causes
that illness rates and severity vary from place to place,
and that the values underlying medical research, practice,
theories and knowledge are deeply biased by the
practice situations and social characteristics of the dominant
group of medical professionals-physicians.”
J. Lorber. Gender and the Social Construction of Illness. Sage
Publications, Thousand Oaks, CA 1997. Quoted by Bird CE in
Previous experiences and
Prejudices and misconceptions.
Modern Scientific Investigation:
1940’s to 1980’s
The Bikini View of Women’s Health
The New Science of Gender-Specific Medicine
And the Beginning of the Genomic Era
Is it ever possible to separate what is hard-wired into the organism by virtue of biological sex and
what is the result of the impact of other factors
on the phenotype?
(It is impossible to separate the organism from its experience.)
“There is no gene-controlled inheritable trait that cannot be altered by the environment…Humans enter the world as a work-in-progress…Nature/nurture is not an either/or duality but, rather, represents a both/and type of complementarity.”
The Complex Dance Between the Genome
Leonard Schlain. Sex. Time and Power. Penguin Books. New York. 2003.
The New World of Genomic Science
The White House announces the completion
of a rough draft of the human genome.
April 14, 2003:
The Human Genome Project announces
a much more complete and accurate version.
Gender and the Genome:
Why do we have two sexes?
How do they differ?
Which is hardier?
The discovery of the gynandromorphic
zebra finch: this bird has male plumage
and a testis on the right side of the body
and female plumage and an ovary on the left side.
the brain was also sexually dimorphic; brain
tissue on the right was genetically male and
that on the left female. The hormonal milieu
of the bird was obviously homogeneous.*
*Agate RJ et al. Proc. Natl. Acad Sci USA100:4873 2003
*Ross MT et al. The DNA sequence of the human X chromosome. Nature 434:325-337. 2005.
“Functional or developmental themes have rarely
been ascribed to whole chromosomes in eukaryotes.
instead, individual chromosomes appear to contain motley
assortments of genes with extremely heterogeneous patterns
of developmentally regulated expression.
We speculated that the human Y chromosome might be a
functionally coherent exception…”*
*Lahn BT and Page DC. Functional Coherence of the Human Y chromosome
Lahn BT and Page DC. Functional Coherence of the Human Y Chromosome. Science 278:675-680.1997
*Aitken RJ and Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction
Given the complexity of how the phenotype is determined, how powerful/useful will the delineation of an individual’s genome be in predicting disease and in choosing therapy?
“Skepticism about genomics runs high….
Some …perceive genomics research as a low-yield
investment at best and as a dangerous
opportunity cost at worst, which undercuts efforts
to address social and environmental causes
of ill health.”
Khoury MJ et al. Am J Prev Med 33(4).310-317.2007
“The question of how genes are defined
and regulated is deceptively simple.
The emerging picture of gene regulation
depicts interdependent layers and webs
of control consisting of interactions of DNA with
regulatory proteins and RNA molecules that are
akin to the interactions that occur
in computer circuitry.”*
Feero WG et al. N Engl. J. Med 362:21.May 27, 2010
Morse A. Searching for the Holy Grail: the Human Genome Project and Its Implications.J Law
“The idea that the human genome can be the Rosetta Stone for disease ignores physical, chemical and environmental factors.*
Keller EF. Master Molecules, in ARE GENES US? Carl F. Cranor ed. 1994.
What is the impact of biological sex
on gene expression?
*Yang X et al. Tissue-specific expression and regulation of sexually dimorphic
Genes in mice. Genome Research.16:995-1004.2006
“We saw striking and measurable differences
in more than half of the genes’ expression pattern
between males and females. We didn’t expect that.
no one has previously demonstrated this genetic
gender gap at such high levels.”**
**Thomas Drake, C0 investigator
*Yang et al. Genome. 2006
Is manipulating the genome
interfering with evolution or
by definition, a continuation
of the process?
Evolution is no longer
With the advent of
we can- and are- changing very nature
of created life.
Engineering the characteristics of new
(human?) beings prepared for specific
functions (like war, for example)
Prolonging the life span indefinitely
Creating new biological systems capable
of reproduction (and if this is so, also
capable themselves of evolution)
“If the molecular, cellular, and genetic machinery
used to conceive, develop, and operate a human
were designed rather than the result of evolution,
humans would be different
and life would look different.”*
*Olshansky et al. What if Humans were Designed to Last?
The Scientist. 21(3).28
What are scientists
“I chide Goldblatt* for the
incredible naiveté he and the
Defense Sciences Office displayed
in not thinking its plans to enhance
humans would arouse controversy….
didn’t it occur to anybody that you
were playing with fire?”
(in Radical Evolution)
*Michael Goldblatt, former head of the Defense Science Office
“My guess is that if the question of human extinction is
ever posed clearly, people will say that it’s all very well to
say we’ve been a part of nature up to now, but that at this
turning point in the human race’s history, it is surely essential that
we do something about it; that we fix the genome to get of rid
of the disease that’s causing the instability, if necessary, we clone
people known to be free from the risk, because that’s the only way
in which we can keep the human race alive.
A still, small voice may at that stage ask, but right does the
human race have to claim precedence for itself. To which my
guess is the full-throated answer would be, sorry, the human
race has taken a decision, and that decision is to survive. And,
if you like, the hell with the rest of the ecosystem.”
Sir John Maddox,
Former editor of Nature
The ability to create living
organisms from inert chemicals.
These new entities will probably
be capable themselves of reproduction
and of evolution into new
Venter’s group has just reported the design, synthesis
and assembly of a genome and its transplantation into
a recipient cell to create new cells that are controlled
only by the synthetic chromosome.*
Gibson DG et al. Sciencexpress./www.sciencexpress.org/20 May 2010/Page 1.
"Ever since the discovery of nuclear fission, the possibility of powerful explosives based on it had been very much in my mind, as it had in that of many other physicists. We had some understanding of what this might do for us in the war, and how much it might change the course of history.”
“I am become death,
destroyer of worlds.”
Professor of Genetics at Harvard Medical School
Director of the Center for Computational Genetics.
“…synthetic biology shares the potential…to generate
new entities that reproduce and evolve at will.
Whether we believe that these are immediate, distant
or imaginary threats, the concerns are real….in addition
to a code of professional ethics for synthetic biologists,
we need to watch for the rare cases where they transgress.”
“Given the momentum and international character
of research in synthetic biology, it is already
too late to impose a moratorium, if indeed one
was ever contemplated.”*
Tucker and Zilinskas: The Problems and Perils of
Synthetic Biology. In The New Atlantis. A
Journal of Technology and Society.
Prometheus, who gave men fire.