Hello, I’m Alan Guttmacher.
I’m the Director of the Eunice Kennedy Shriver
National Institute of Child Health and Human Development
at the National Institutes of Health.
And I’m going to talk with you today about birth defects and about
the role of research in understanding birth defects in treating them
and in preventing them.
First I’m going to say something about the basic facts about birth defects,
then talk with you about an example where research has already
made a difference in terms of preventing birth defects.
I’m also going to talk about how we use model systems to
study development which is very important in understanding
birth defects.
And I’ll talk then about the role of systems biology and of
chemical genomics in understanding birth defects and in coming up with
new treatment and prevention measures for them.
And finally, I’ll talk with you some about other research opportunities
in birth defects.
Probably the first basic fact to get across about birth defects
is that the term “birth defects” is a terrible term in many ways.
It’s the one that we’ve used scientifically for years,
it’s the one we still use, but the problem with it is
that by calling it a defect, first of all we give, I think,
unneeded stigma to kids and families who are born with a birth defect.
But also, sometimes it keeps science from advancing.
This is really about human variation.
And part of human variation can be to be born with certain problems,
which we label as “birth defects.”
What we mean when we say 'birth defect' is something that causes
structural changes in one or more parts of the body and, of course,
is present at birth.
We distinguish major from minor birth defects:
major birth defects being those that have a serious adverse effect
on health, development, or functional ability.
In the U.S. about 3% of all babies are born with one of these
major birth defects.
Birth defects account for greater than 20% of all infant deaths in the U.S.
They are also associated with higher risks of illness and of
long term disability— for those who are born with birth defects and survive.
Major structural birth defects include those that affect
the heart, the limb, the face, the nervous system, and sometimes
other parts of the body as well.
What those numbers don’t show, what those definitions don’t tell us,
is about the impact of birth defects in the lives of individuals
who have birth defects and their families
which of course, can be major or can be less major.
And that’s not just depending upon the nature of the birth defect itself,
but it also depends upon the individual and their resiliency,
it depends upon the family, and how they view the specific birth defect.
So birth defects— while they have biological causes in terms of
their impact upon the lives on individual and families--
it’s not just a question of biology, it’s a question of other aspects
of the human condition as well, really.
Research has played a critical role for many years in better understanding
birth defects and already in terms of treating them and even preventing
some birth defects.
One recent research success story relates to neural tube defects.
Neural tube defects are multifactoral,
that is they’re caused by a combination of many different things.
Some of them dietary, we believe.
Certainly there are some genes that are involved and people who
are born with certain genetic variations have an increased likelihood
for being born with a neural tube defect but there are other, again, dietary and
other kinds of factors, not all of which we yet understand,
which play a role in causing neural tube defects.
Neural tube defects can be quite devastating; they affect the brain,
the spinal cord.
So, depending on how severe they are, they can have quite an effect
on the individual.
Research a number of years ago
showed that folic acid supplementation
might prevent this specific birth defect, neural tube defects, and the fact,
based upon that research, the U.S. some years ago began to fortify
grain products to include extra folic acid or folate,
and because of this supplementation, the prevalence of neural tube defects
in the U.S. decreased by more than 25%--
simply by adding this important vitamin
to food that we take in normally, particularly bread.
This is a great success story.
We’d like to have other such success stories so we could
lessen the burden to individuals and to society in terms of birth defects.
One way to do that is to use model systems to study development
by model systems-- of course, I mean organisms other than humans.
It’s hard to study human embryology, we do it but it has its own difficulties.
And there are other kinds of model organisms that can help us
understand development in a way that is certainly applicable to humans but
allows us to really get much more understanding of the way
that organs form.
One very useful model organism is the zebrafish.
The zebrafish is a great model for figuring out how things
develop embryologically.
Like humans, zebrafish are vertebrates,
so they have central nervous systems much like ours et cetera.
But they mature much more quickly-- the embryos-- than is true for humans,
so that there’s much less time involved in doing any kind of research.
Zebrafish lay hundreds of eggs at weekly intervals,
so that makes them very amenable to large scale chemical and genetic
screens to understand embryology, and they’re transparent
so that you can actually look directly at the developing organs.
And in this video that you see now you can see obviously
since they speed it up somewhat
but you can see the zebrafish embryo developing and this is, in fact,
what scientists can see by looking through their own microscopes.
They can look at multiple zebrafishes developing.
We can do various things to perturb the development of the zebrafish,
whether it be to introduce some kind of chemical into the water
in which they’re swimming or to manipulate the genes of the zebrafish
in ways that allow us to understand exactly what’s happening—
because we’re able to observe it happening.
Systems biology is another tool for understanding the formation
of organs in the embryo, and therefore, to really let us understand much better
than we do today exactly how birth defects come to be.
The systems biology approach allows us to look at
gene regulatory networks.
They are really quite intricate but very important in terms of
controlling the switches that turn on and off certain parts
of embryo formation, in a certain timed manner that’s very important.
So systems biology, by integrating
these entire networks of genes involved,
allows us to look at the complexity of organ development,
whether it be in model organisms or in the human.
We know that its (the) interplay of multiple systems that is
really important to understand the complexity of development.
Chemical genomics is another tool which is very useful,
particularly in terms of developing new drug targets and new effective
drugs for birth defects.
Chemical genomics allows us to use high throughput screening techniques
of small molecules such as folate, and that can yield new therapies
to really lessen the impact of birth defects.
There are already several examples that are in development
or actually have already been developed besides folate.
One of them is the use of losartan for Marfan syndrome.
A fairly common kind of birth defect that affects the structure of
many parts of the body.
There’s also the development of an mGluR5 antagonist
for Fragile X syndrome,
which is an inherited condition that leads both to intellectual and
developmental disability and certain structural changes in people
who are born with it.
As well as that there are also GalK inhibitors for galactosemia
which is not something that causes a structural birth defect, so much as
it causes significant developmental problems which are present
at birth in that it’s an inborn error of metabolism, as we call it.
Something that is present at birth in the way we metabolize things
and that’s another very useful approach that again has come out of
this chemical genomics approach.
You can see on the screen now robots in the chemical genomics facility
using this very high throughput approach
whereby one can screen potentially
tens of thousands, if not hundreds of thousands, of small molecular
compounds in a very short interval to see whether they have actually—
either an antagonist or an agonist involved in the pathways that you’re
particularly interested in for a given birth defect.
There are many other research opportunities on the horizon,
we think that will allow us to again better understand birth defects
and be able to prevent and treat them more effectively.
One of our goals is to develop a complete genetic map of
common and rare structural and functional birth defects,
if we have that complete genetic map that gives us many more possible
drug targets to intervene with.
Another idea is to delineate the environmental interactions
with the genome.
That is, things that cause birth defects:
whether they be radiation exposure, chemicals, drugs,
other kinds of things, to understand exactly how they interact
with the genome of both the mother and of the fetus, because we think
both genomes are important.
And again, the interaction between these environmental factors and
those two genomes that leads to birth defects in certain situations.
Another approach is to develop new, noninvasive, tools to assess the
development of the human in utero.
It would be wonderful if we could somehow observe human development
the way we can the zebrafish.
We’ll never be able to do quite that, but it would be useful to have
better tools for noticing what’s going on in human development
actually as it's happening rather than having to rely completely
on other kinds of models.
Another important research opportunity comes from the fact that
the vast majority of drugs used by pregnant women have never been
studied in pregnancy.
These can be drugs which a woman is using because of some
complication of pregnancy.
Maybe a woman develops high blood pressure
during pregnancy and needs to be
given a drug to control her blood pressure both for her own health
and for the health of the fetus or it can simply be a drug,
maybe even an over-the-counter drug, that the woman was using before
she became pregnant because of some underlying medical condition
or some health concern and she continues to use during pregnancy.
Whichever category of drug, the chances are it’s never been studied
in pregnancy so we don’t truly know the effects on the fetus.
This is a huge— not only research opportunity—
I would say, but a huge responsibility.
We need to do a better job of studying these drugs when they’re
used in pregnancy when both women can be vulnerable and certainly
the fetus is particularly vulnerable.
So, in summary, I hope that I’ve shared with you pretty
convincing evidence
that research has already yielded an important understanding that
really does help us prevent and treat birth defects.
But that we’re at the beginning of an era where we have
new scientific tools, new kinds of approaches, having the
human genome in hand, having the power of chemical genomics,
these kinds of approaches that are recent tools for us.
That we are at the beginning of an era where we believe we can harness
these kinds of new tools to have a completely new, and much more
in-depth, understanding of exactly how birth defects come to be and,
based upon that understanding, have much more effective strategies
for treating and for preventing birth defects.
If you’d like more information about this and related topics
you should visit the NICHD--
that is the National Institute of Child Health
and Human Development website.
Thanks very much for your attention to this and we welcome your interest
again in treating and in preventing birth defects.