berlin v 12 september 2015 by Marianne Legato M.D. at physician

1. Gender-Specific Medicine in the Genomic Era:
What Are the Questions? How Do We Find the Answers?
Marianne J. Legato, M.D.
Emerita Professor of Clinical Medicine, Columbia University
Adjunct Professor of Medicine, Johns Hopkins

2. “Nothing endures but change.”
Heraclitus

3. “Over the last twenty years,
I have come to appreciate
an important meta-idea;
that the power of ideas
to transform the world
is itself accelerating.”
Kurzweil R. The Singularity is Near. Viking. 2005. p. 3

4. The past fifty 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.

5. Transformative Changes
in 21st Century Biomedical Science
• Description and manipulation
of the genome and the factors
that regulate gene expression
• Synthetic biology
• Technological advances: that
expand human competence
• Robots of increasing
complexity

7. Malthus
1766-1834
Lamarck
1744-1829
Darwin
1809-1882
“I am strongly inclined to
suspect that the most frequent
cause of variability may be
attributed to the male and
female reproductive elements
having been affected prior to
the act of conception.”
"The great and
unlooked for
discoveries that have
taken place of late
years...have all
concurred to lead
many able men into
the opinion that we
were touching on a
period big with the
most important
changes, changes that
would in some measure
be decisive of the
future fate of
mankind."
"The environment affects the
shape and organization of
animals, that is to say that
when the environment
becomes very different, it
produces in course of time
corresponding modifications in
the shape and organization of
animals."

8. Nirenberg
(1968)
Venter
“The genetic
code is now
essentially
deciphered.”
"Genome design is
going to be a key
part of the
future. ”
Church
“Today we are at the point…
where we humans can
reduplicate and then improve
on what nature has already
accomplished.”

9. When one considers the number of species
of molecules that are required for the
synthesis of a single molecule of protein
and the fact that the cellular machinery
that participates in the assembly process is
complex, heterogeneous, and not reliable,
the problem of synthesizing protein with
precision seems formidable. To synthesize
one molecule of protein composed of 400
amino acid residues, 400 AA-tRNA
molecules must be selected in the proper
sequence. For the synthesis of the
corresponding molecule of mRNA, at least
1206 molecules of ribonucleoside
triphosphate must be selected in sequence.
(Marshall Nirenberg:
Nobel Lecture.1968)
What Are The Challenges of Genomic Manipulation?

10. The Genomic Era
Is manipulating the genome
interfering with evolution or
by definition, a continuation
of the process?

11. “I can understand why many observers
do not readily embrace the obvious implications
of what I have called
the inherent acceleration of the rate of evolution,
with technological evolution as
a continuation of biological evolution.”
Ibid. p 7

12. Some Questions For
The Gender-Specific Community
1. 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 development, hormones and
environment on the phenotype?
2. What will be the consequences of our
ability to modify the human genome?
What role will synthetic biology play in the
nature of life on this planet?
What is the impact of biological sex on gene
expression? Will we be able/tempted to change
that impact?
3. What are the molecular mechanisms
underlying variations in sexual identity?

13. Question 1:
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 development,
hormones and environment
on the phenotype?

14. What Defines The Phenotype?
Nature or Nuture?
• From the first conception of gender-specific medicine,
opposing camps of 1990’s formulated the question and
argued about the answer.
• The expanding science of epigenomics makes it evident
that the environment modifies and refashions gene
expression from conception to the end of life. It is
impossible-and irrelevant-to separate the two.

15. “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.”
Leonard Schlain. Sex. Time and Power. Penguin Books. New York. 2003.
The Complex Dance Between the Genome
And Experience:
Environmental Epigenomics.

16. “Our ‘innate‘ love affair with the nature versus
nurture argument is not over but should be.
A novel synthesis emerges from the two originally
conflicting positions, which includes elements of
both, resulting in essence from resolution of the
original tensions caused by the polarity.”
James C. Woodson. Socioaffective Neuroscience & Psychology 2:17334. 2012

17. Question 2:
What will be the
consequences of our
ability to modify the
human genome?

19. Evolution is no longer
“natural selection”.
With the advent of
genetic engineering,
we can - and are - changing the
very nature
of created life.

20. Biological evolution is too slow for
the human species. Over the next
few decades, it’s going to be left
in the dust.
Nature, and the natural human
condition, generates tremendous
suffering. We have the means to
overcome that, and we should
deploy it.

21. What is the impact of
biological sex on gene
expression?
Will we be able to
change that impact?

22. Sexual Dimorphism is Achieved Not
Only by Gonadal Hormones but by the
Direct Effect of X and Y Genes.
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

23. Sex Impacts Gene Expression*
“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.”**
*Yang et al. Genome. 2006 **Thomas Drake, C0 investigator

24. Genomic Science and Sex
• Will it be an advantage to
retain two sexes?
• If we eliminate or modify
biological sex in new forms
of life before we
understand the nature and
extent of its impact on
gene expression, what will
be the consequences to
form and function?
• Does the study of the
impact of sex on gene
expression deserve more
attention? Genomic
scientists are rarely
considering the impact of
biological sex on their data.

25. Marble Statue, Sleeping Hermaphrodite.
Rome, Museo Nazionale Romano -
Massimo Palace National Museum,
Question 3:
What are the variations of the sexed
individual?

26. Terms and Definitions
– Intersex: discordance between chromosomal
sex and genital anatomy
– Gender Identity
Transgender/transsexual: an individual’s
pervasive and persistent conviction that he
or she is not the sex that anatomy and even
chromosomal identify indicate
– Sexual Orientation
Homosexuality/Bisexuality

27. The sex-specific brain:
the ultimate erotic organ
“If you want to know what sex a person is, simply ask him”
(Eric Villain)

28. How much do we know about
the mechanisms that produce these
variations on human sexuality?
If treatment is indicated, what
are the options?
What research needs to be done?
Questions Without Answers

29. Disorders of Sex Development
Each case is unique and should be assessed by a
multidisciplinary team. Yang JH et al. Pediatric
Urology.75:153.2010
Surgical correction of the intersex child? If so, when?
Izquierdo G and Glassberg KI.Urology.42(3).232.1993.
Timing and degree of exposure
of developing brain
to androgens is crucially
important in determining
gender identity.

30. Is there an underlying
biological mechanism for
homosexuality?
How do we explain the
absence of any DNA
markers of homosexuality
and the heredibility of the
phenomenon?

31. “Epi-genetically Canalized”
Sexual Preference?*
Rice WR et a. Quarterly Review of Biology.87 (4).343
 There has been no convincing molecular genetic evidence that
homosexuality is familial
 Maternal antibody theory cannot explain homosexuality in
women
 Rice et al postulate genome-wide epi-marking that occurs
early in development. Epi-marks influence androgen signaling
and are manifest across all androgen-sensitive tissues at the
pre-implantation blastula stage,
 Theory: one or more stronger than average epi-marks (called
the sexual preference epimark) canalize sexual preference
very early in development- Neither the genitals
nor sexual identity are affected.

32. Other Theories of
the Basis of Sexual Preference
 Impact of early sexual experience.
Pfaus JG et al. Arch.Sex.Behav. 41:31.2012.
The interactionist stance: the neuroplasticity
underlying learning continually changes how
subsequent experiences will uniquely affect each
individual. Woodson. Socioaffective Neuroscience & Psychology 2:17334.2012
Dual-gender macrochimeric tissue discordance
Hanley BP. Hypotheses in the Life Sciences. 3:63.
Differences in cerebral asymmetry and functional
connectivity between homo and heterosexual
subjects: (MRI and PET data)
Savic I.PNAS.105.9403.2008

33. June 12, 2014
(NPR) – How is it that we
define a human? Is it our
body? Our genome? Our
behaviors? Our self-
awareness? Our compassion?
Our minds? All of these and
then something more? What
now may be obvious to most
people about being human will
become less so as we become
progressively more
integrated with technology
both inside and outside our
bodies.

34. Health Care in Your Lifetime
• The role of the physician
will continue to change
exponentially.
• Optimal patient care will
involve experts in a whole
new spectrum of
disciplines. Care will
necessarily include
assessment by experts in
fields we do not currently
access.
• Our idea of what it means
to be human will change
profoundly.