Birth Defects: The Role of Research

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.

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