Gender-Specific Medicine: Achievements and Challenges - Elsevier

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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?”





Traditional Biomedical

Research Has


Made men normative

for the
entire population.
Paradoxically, there has not
been a systematic consideration
of
their

unique, gender
-
specific
features.



Not grappled with the
extraordinarily difficult and
most important issue of teasing
out what characteristics are
hard
-
wired as a result of
biological sex and which are
the consequence of social
forces and environment.

Critics of the biomedical model

have demonstrated that:


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

10.1016/50277
-
9536(98)00420
-
X


What Influences “Health”?


Biomedical and sociologic experts often disregard and even disparage
each other, particularly when funding is scarce.



Assumptions
about health influence practice (The notion that women
are relatively immune to coronary artery disease is still deep seatd in
medical practice.)



There are
gender differences

in


health behaviors of men and women


the level of attention given to preserving male and female health


the societal roles expected of males and females.


These patterns may shift over time.



Anne Fausto
-

Sterling: without absolute social equality we cannot know
the absolute differences between men and women.



What Influences Biomedical
Investigation?


Public interest


The investigator:

Innate ability.


Previous experiences and

training.


Prejudices and
misconceptions.


1990
-
2010: How Far Have We Come

and Where are We Now?


We are more aware of the extent and complexity
of the
sex and gender specific properties

of living
organisms.



We are exploring how the intricate dance
between the genome, hormones and the
environment creates the
phenotype.




We are inserting mechanical components into
humans, including into their brains. We are also
creating completely mechanical entities;
robots

capable of heretofore unimagined complex
maneuvers.



The new age of
synthetic biology

is transforming
our understanding of what constitutes life. For
the first time in the history of the world we have
the power to generate new forms of life,
themselves capable of reproduction.




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

2000:

Genomic

Medicine

2003:

ENCODE


1994
-
2000

Gender
-

Specific

Medicine

1988
-

Direct

Investigation of

Women

2010:

Synthetic Biology


2000:

Robots

Some Important Issues


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?



What is the impact of biological sex on gene
expression?




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?



To what extent will mechanical parts augment
human abilities? What does it mean to be ‘human’?



What role will
synthetic biology

play in the nature of
life on this planet?



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?


“Sex
-
specific?”

“Gender
-
specific?”

(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.”

Leonard Schlain. Sex. Time and Power. Penguin Books. New York. 2003.

The Complex Dance Between the Genome

And Experience:

Environmental Epigenomics.

How Environmental Factors Impact
the Phenotype


Environmental factors act by


mutating promoter and coding regions of genes


modifying CpG methylation at critically labile genomic
regions. (
Waterland R and Jirtle R. Nutrition 20:63.2004)



Epigenetic mechanisms include chromatin folding and
attachment to the nuclear matrix, packaging of DNA
around nucelosomes, covalent modifications of histone tails
and DNA methylation.
(Dolinoy DC and Jirtle RL.Environ. Mol
Mutatgen.49:4.2008)



Regulatory small RNA’s and micro RNA’s impact gene
transcription.

(Matzke M and Birchler J. Nat Rev Genet 6:24.2005)

How Experience

Changes the Brain


Neural changes associated with
environmental enrichment
: increase in brain
size, cortical thickness, neuron size, dendritic branching, spine density,
synapses per neuron and glial numbers.
(Kolb B and Whishaw IQ. Annu Rev
Psychol.49:43.1998)



Modulation of Experience
-
dependent Change


Age:

neuronal loss and dendritic growth: an area of controversy.


Sex hormones:

essential to sex
-
specific development of the brain and to
maintain the sex
-
specific characteristics of the brain throughout life.
(
Stewart J and Kolb B. Behav.Neural Biol.49:344.1988 and Brain Res.654:149. 1994.)


Neurotropins


Stress:



chronic excess of glucocorticoids is toxic to neurons.
(
Sapolsky RM. Stress,
the Aging Brain and Mechanisms of Neuronal Death. MIT Press. 1992)


Early life experience and major stressful life events produce
dysregulation of serotonergic systems
.

(Gardner LK et al. Brain Research
Elsevier.2009)





June 26,2000
:

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.


The New World of Genomic Science

Gender and the Genome:

Why do we have two sexes?

How do they differ?

Which is hardier?



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

The X chromosome*


Contains 1,098 genes; only 4% of all human genes:

gene density is low and gene length is lower than any other
of the chromosomes annotated to date. (Furthermore, only
33% of the chromosome is transcribed.)



Only 54 of these genes have functional homologues on the
Y chromosome.



Many of the genes that have to do with intelligence may be
located on the X chromosome and may be closely linked
with a gene dictating preference for intelligent males.



Almost 10% of diseases with a mendelian pattern of
inheritance are X
-
linked.


*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

Science.278:675
-
680.1997

The Y Chromosome:

a New View

The Y Chromosome:

Revising the Wasteland Model*


It is an unique chromosome
:


Common ancestry and persistent relationship with the X chromosome


Present only in males


Does not combine with its partner along 95% of its length (called the NRY
or non
-
recombining portion of the Y chromosome
)


Tendency of its genes to degenerate during evolution


Unique coherence of gene content




Contains 78 genes (almost double the previously known tally) which make up <1% of the
genome.

They encode only 28 distinct proteins.



The Y chromosome
can repair itself as a result of its palindromic structure.
A backup
copy of each of the genes they contain exists at each end of the sequence.


Lahn BT and Page DC. Functional Coherence of the Human Y Chromosome. Science 278:675
-
680.1997

Male Driven Evolution*


Almost all new mutations are derived from the
father.
(Makova KD and Li WH. Nature 416:624
-
26.2002)



Oocytes spend most of their lives in relative dormancy .
Sperm are produced in huge numbers and have much
higher metabolic requirements.



Male: female mutations in primates is about 3
-
6:1.
Mutations result from


Replication errors


DNA fragmentation



Variability in the male germ line creates the genetic
diversity that fuels the evolutionary process.

*
Aitken RJ and Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction

122:497
-
506.2001

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.”

Combining Genomics with Epidemiology:

Balancing Population Based with Individually
Targeted Prevention/Treatment Strategies.


Is increasing attention to genomics
useful for the
public health?



Will it widen the gap between richer and poorer members of society?


Will it reinforce racial stereotyping?


Will it lead researchers to miss factors that contribute to disparities more
substantially than genomics?





The new science of
human genome epidemiology
:
assesses*


Prevalence of gene variants in different populations


Magnitude of disease risk associated with gene variants


Magnitude of disease risk associated with gene
-
gene and gene
-
environment
interactions


Validity and effectiveness of genetic tests for screening and prevention.


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

The Human Genome Project:

Is It the Holy Grail?*:

The Notion of Biological Determinism




“The assumption that genes are the carrier of our destiny...
places

reductionist

explanations to behavior above all
others and, in so doing,
allocates other causes such as
environment to subsidiary roles
.”



Genes are not the determinant mechanism in a biological
process,
but part of an interaction between the genes and
the organism as a whole.



Organicism:

a more complex and less popular view, which
maintains that reductionism is inadequate to explain living
systems. It maintains that one must look at the
organizational structure of the organism, not just its
disparate parts.

Morse A. Searching for the Holy Grail: the Human Genome Project and Its Implications.J Law

& Health.13:1
-
34.1998.

“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?



The Genetic Gender Gap: The
Sexually Dimorphic Gene*


Thousands of genes showed sexual dimorphism

in liver, adipose
and muscle; hundreds of genes were sexually dimorphic in
brain.



These differences are
highly tissue specific
; thousands of genes
identified were involved in tissue
-
specific biological functions
and/or pathways relevant to common diseases and showed
tissue
-
specific chromosomal enrichment.



Only 27 genes showed consistent direction , i.e. all female or all
male biased in all tissues.



A significant portion of sexually dimorphic genes are located on
the sex chromosomes, but some are carried on autosomes as
well.

*Yang X et al. Tissue
-
specific expression and regulation of sexually dimorphic

Genes in mice. Genome Research.16:995
-
1004.2006

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

The

Genomic Era


Is manipulating the genome

interfering with evolution or

by definition, a continuation

of the process?



What Scientists

are Doing


Taking genes out and
inserting others.



Creating biologic
specimens capable of
reproduction.



Giving us an increasingly
precise picture of who we
are and the possibility of
changing it.



Evolution is no longer


“natural selection”.

With the advent of

genetic engineering,

we can
-

and are
-

changing very
nature

of created life.

Imagine:


Human cloning


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)

Genomic Science and Sex


Will it be an advantage to retain
two sexes?



If we eliminate biological sex in
new forms of life before we
understand the nature and
extent of its expression on
genes, 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 not always
considering the impact of
biological sex on their data.




“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


worrying about?

Consider the Impact Of

Genomic Science On


The environment



Economics



The nature and number of living beings



The redistribution of power (planned and
unplanned)




I chide Goldblatt* for the

incredible naivet
é

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?





Joel Garreau





(in Radical Evolution)



*
Michael Goldblatt, former head of the Defense Science Office

What Scientists are Saying


We are changing the rate and
mechanisms of the evolution of living
things profoundly.



If there is a choice between preserving
the earth in a viable state or continuing
the human race, we will probably opt to
continue the race.


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

Synthetic biology:


The ability to create living

organisms from inert chemicals.


These new entities will probably

be capable themselves of reproduction

and of evolution into new

forms.

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.


Venter’s Achievement:

Reactions


Obama

urges Presidential Commission for the Study of Bioethical Issues to
focus on the research: “This development raises the prospect of important
benefits….at the same time it raises genuine concerns…”.



George Church
: “This milestone and many like it should be
celebrated…But…the semi
-
synthetic myobacterium is not changed from the
wild state in any fundamental sense. Printing out a copy of an ancient text isn’t
the same as understanding the language.”



Arthur Caplan
: “Venter and his colleagues have shown that the material world
can be manipulated to produce what we recognize as life…Christianity, Islam
and Judaism, among other religions, have maintained that a soul constitutes
the explanatory essence of at least human life….All of these…views are cast
into doubt by the demonstration that life can be created from non
-
living
parts…”



Martin Fussenegger
: “Venter…calls this ‘going from reading our genetic code
to the ability to write it.” It may sound scary, but there is no guarantee that
what will be written will make sense.”


"
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.”






Doctor Atomic

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.”

George Church

Doctor Genomic


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.

What Are Areas of Special Interest

As We Go Forward?




Focusing a
gender
-
specific lens on men
, so that we can better
understand their greater vulnerability compared with women.



Expanding the current science of gender
-
specific medicine and
testing
its value in clinical practice.



Urging the exploration of the
impact of biological sex

on both the
naturally occurring and synthetically created/altered genome.



Encouraging the
colloquium

between jurists, ethicists and scientists
about the legal and moral implications of genomic science and
synthetic biology.