Download Marianne J. Legato "Designing Clinical Trials"

Designing Clinical Trials:
Is the Inclusion of Women
Popular
Necessary
Economically Feasible
/Sound
Safe for Women
Always Possible
Objections to Including Women
in Clinical Investigation
Ø Many investigators and practitioners believe “gender medicine” is a
politically motivated and scientifically indefensible discipline.
Ø Including two sexes increases the expense of most studies and
ultimately strains the already restricted amount of research funding
available.
Ø Including the premenopausal woman in clinical studies is potentially
dangerous to the reproductive function of the subject and to any child
conceived during the course of the trial.
Ø The trajectory of the same diseases is often temporally quite different
in men and women, making inclusion of both sexes fraught with issues
like associated conditions in the older patient, hormonal differences,
and differences in the physiology of aging.
Two New Phenomena
Are Changing Our Approach to Clinical
Investigation
ØThe acknowledgement of the fact
that men and women have
significant and widespread
biological differences. (1990-present)
ØOur growing sophistication in our
understanding of the genome and the
incorporation into research of ever-more
effective ways of measuring its impact on
human biology. (2000-present)
Some Important Issues
Ø 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?
Ø 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?
Ø What is the impact of biological sex on gene
expression?
Ø To what extent will augmented or newly created
tissues/organs change the human phenotype? What
does it mean to be ‘human’?
Ø What role will synthetic biology play in the nature of
life on this planet?
“Sex specific?” “Gender Specific?”:
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?
Genes and Gender:
There are Striking Effects of Gender on Gene
Expression
Ø Sexually dimorphic genes exist in mouse liver, adipose, brain and
muscle tissue: differences range from a few hundred to more than
10,000.*
There is tissue-specific expression and regulation of these genes
in spite of nearly identical genome sequences between males and
females.
Ø Not only the X&Y chromosomes but autosomes are also enriched
with sexually dimorphic genes in a sex-specific fashion.
Ø Many of the genes identified are implicated in common diseases
in which susceptibility is sex-biased (neuropsychiatric disorders,
atherosclerosis, obesity and drug responses.)
*Yang et al. Genome research.16:995.2006
Other Factors Complicating
Genomic Science
Ø The role of mitochondrial DNA on phenotype: changing
the mitochondrial genome in female fruit flies altered
expression of only a handful of genes; in males, more than a
thousand genes showed changes in expression.* (Innocenti
et al. Science 10.1126.2011)
Ø Impact of the microbiome on phenotype:
what is the impact of sex
on the function of the microbiome?
1990-2010: How Far Have We Come
and Where are We Now?
Ø We are more aware of the extent and complexity
of the sex and gender specific properties of living
organisms.
Ø We are exploring how the intricate dance
between the genome, hormones and the
environment creates the phenotype.
Ø We are inserting mechanical components into
humans, including into their brains. We are also
creating completely mechanical entities; robots
capable of heretofore unimagined abilities.
Ø 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.
Genomics: Reinforcing the
Importance of Gender in Biology
We are only beginning to unravel the genetic
basis for the gender-specific differences in
normal function and in the experience of
disease.
The story is far from complete but as data
accumulate it will be apparent that the
economy of genes in both health and disease is
profoundly impacted by biological sex.
Many of the unanswered questions about the
reasons for the differences in risk factors,
symptoms and the response to therapy in men
and women with disease are beginning to be
answered at a more fundamental level
than observational studies have been able to
provide.