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An
Interview with Miguel Weil
 Dr. Miguel
Weil first introduced himself to FD Hope at the NIH
conference on Inherited Dysautonomias, initiated by FD
Hope, in October 2002. He had already distinguished
himself during the question and answer session of the
conference with his passionate, moving, and probing
questions about the relevance of research for the children
and adults with FD. Not only is he a dedicated, first-rate
scientist, he is the father of Nir, a fourteen year old
with Familial Dysautonomia. We were delighted, a year
later, to receive his grant proposal for
research into the mechanisms of the FD mutation. When
funding was insufficient to award the full grant proposal,
he suggested we fund the portion of research to be
conducted by Dr. Gil Ast, as the most important first step
to the full project. In April, 2005, we were able to
approve funding for Dr. Weil's research. We spoke by phone
about his research, his family, and his hopes for FD.
What can you tell us about your
research?
My goal is to find out how the FD
mutation affects development and why part of the
peripheral nervous system does not develop normally, why
cells are lost. The most common FD mutation causes a
defect in the production of the FD protein IKAP. In more
than 99% of FD individuals the mutation is inherited from
both parents and thus appears on both copies of the gene.
More specifically, the mutation results in a smaller than
normal gene product (a mutant IKAP protein). This mutation
is tissue specific which means it affects some tissues
more than others. Brain tissue and presumably neurons of
the autonomic and sensory nervous system are most
susceptible to the mutation. The aim of our research is to
understand the meaning of this FD mutation in IKAP and
its effect in the development and maintenance of the
specific neurons that arc reduced or missing in FD
individuals.
How do you plan to do this?
We have learned from the research
by Gil (Dr. Ast) that the FD mutation is affected by a
primate specific sequence called ALU that is found nearby,
and so this question needs to be addressed in human
neurons but the availability of normal human neuronal
cells is problematic. To solve this problem we plan to use
the potential of established human embryonic and adult
bone marrow stem cells to produce human neuronal cells in
culture dishes and in the developing nervous system of
chick embryos. The developing chick embryos have the
potential to give all the right conditions for human stem
cells to differentiate into the multiple types of neurons
in a few days synchronized with the timing and place of
the chick neural development. In this way we plan to
establish an experimental platform for the study of FD
and other human neurodegenerative diseases in vivo.
In other words, because you
can't experiment on living human nerves, you will "trick"
chick embryos to make human nerve cells to study?
Yes, exactly.
Other labs are working on mice
models of FD, what advantages does this method have?
What our approach could add to a
mouse model is that we arc looking at real human neurons
that are relevant to FD. So we can explore directly the
meaning of FD in human neurons. The mutation results in
abnormal IKAP protein in a specific population of neurons;
it is a human condition, related to being human because of
the ALU sequences. Since the mouse doesn't have the ALU
sequence, a similar mutation in the mouse most likely
won't have the same effect, without the human background
of the gene. The breakthroughs will come by looking at
human neurons, and by manipulating the human neurons.
Growing them more easily will allow solutions to occur
more easily.
What else will you be able to
do with this technology?
This approach could lead us in the
near future to ways that will be feasible to rescue the FD
mutation in neurons derived from stem cells obtained from
FD patients. By establishing this platform, we can study
the effects of the FD mutation and learn why cells are
lost in development, and by understanding the mechanisms
of cell loss, we can understand the effect of the
mutation.
How does that translate into
help for the kids and adults with FD?
There are several ways it will
help the children and adults with FD. First, we could try
to affect the IKAP expression in these neurons and by
doing so recover the potential of FD stern cells in
generating a normal nervous system. This could teach us
how to keep neurons in a child with FD healthy. Then we
could mimic the pathways of why specific neurons are
missing. And we will have ways to extend the life span of
these specific neurons in living FD patients, to reduce
neurodegeneration in FD patients.
Second, it would provide a way to
study the effect of treatments such as tocotrienols and
EGCG in the recovery and survival of FD neurons in the
chick. We could look at the level of gene expression.
Right now it is possible to measure blood levels of IKAP,
but we can't tell if IKAP levels are increasing in the
brains of treated patients. We know that EGCG and
tocotrienols increase IKAP in blood cells, but we don't
know about living neurons. We would not just measure the
levels of IKAP in FD neurons, but see the effect of the
increased levels of IKAP on living FD neurons. We could
make a connection between the molecular levels and effect
of increased IKAP on the specific neurons that are
decreased, or most affected in FD.
Thirdly, when the gene cure is
developed by someone like Gil (Ast), we wont be able to
use a mouse model because of ALU sequence isn't found in
mice genes. We could use the platform that I'm developing
to test gene therapy. Also, we can work with human bone
marrow stem cells, not just embryonic stem cells, so we
could use samples from FD patients and carriers.
Finally, because we could use bone
marrow stem cells from patients, we could come back to the
patient directly for crisis problems. We would test a
battery of therapies by inducing these cells into stress
and see what crisis mean for neurons. Then see how drugs
work or don't at a molecular level and find additional
therapies. We can also do electroplnsiology studies
(looking at how the neurons communicate with each other)
which is nearly impossible to do with neurons grown in a
dish.
What is your dream for FD
research?
To get FD neurons, then we could
start asking the relevant questions that are related to
the FD mutation and understand the role of IKAP in neurons
in general and in those specific neurons hit the most by
the mutation. And once we understand the role of the
mutation in producing the FD phenotype, we will be able to
bring real solution to these individuals. The approach
we're taking is very promising. We are moving in the right
direction.
When do you see the possibility
of a cure becoming a reality?
I hope it will be in my son’s
lifetime. The sooner, the better. For me a cure will be to
be sure that neurodegeneration will stop, that his qualify
of life will not deteriorate. For me this is enough. To
cure FD is to stop the progression of the disease and to
make life easier for individuals with FD. Most of all,
that they will enjoy life. For me, the cure will be that
Nir will keep enjoying life. The minute that he will stop
enjoying life, that’s a worry for me.
Tell me about Nir.
Nir was just over a year old when
he was diagnosed with FD. The doctors did many skin tests
(histamine tests) that turned out negative. Dr. Maayan
(Israeli Dysautonomia Center’s physician) repeated the
test correctly, and with all the other aspects that fit,
she made the diagnosis. Nir is an incredible person. He’s
my hero. He’s the most positive person I’ve ever known and
his positivity is contagious. He wakes up and goes to
sleep with a smile. He sees himself as a boy who can do
anything. He has dreams to become something and the energy
to move mountains. His body suffers so much but his mind
is incredible, unscratched. And this is remarkable. He can
be in crisis, and when he steps out, it’s like nothing
happened. He always looks at the bright side. He’s a joy
to be with and talk with. He’s a happy child. Our
commitment is to keep it that way … I can talk about him
for hours.
What have you learned from
being Nir’s father?
I don’t consider myself without
Nir. I cannot see our family without Nir. It’s
inconceivable. He’s the engine behind all of us. He’s the
candle of our life. I can’t find enough words to describe
him. He’s unique and I’m proud to be his father. He’s an
incredible human being who’s way above all of us, a
different dimension of humanity, in the best way.
How has FD touched your life?
FD touched my life completely and
forever. I'd never heard of FD before, never knew that
something like that could happen or that I was a carrier
of the condition. Since Nir was born, everything changed.
We started to discover ourselves; we never knew we had
such energy and dreams to keep him going. We always knew
he had something special. From the bad news, we took the
good energy and learned how to move mountains and became
experts on this condition. How could it be otherwise?
Having an FD child changes your life in a manner you never
would have dreamed of. Basically, it makes you look at
life very differently than before. We become better
persons. What we get back from Nir is the major thing that
keeps us going. I saw in Nir from the beginning that he
was something special, even with all the problems. We try
to make his life worthy, the best it can be. Life gives
you challenges that are unexpected and hard, and
difficult. The first year was a nightmare. We didn't
expect him to live. He has given us back so much more.
Do you have anything else you'd
like to share?
I can't ask for more than having a
normal life, having some perspective. When we were first
diagnosed, we couldn't plan anything. We had so much to
learn about caring for Nir. Routine for us is a gift; it's
not taken for granted. Every day I work is a joy, because
it means that Nir is well and it means that I can do
research on FD. I'm really lucky I can do these things for
him, and pay him back for all he's given me.
Dr. Miguel Weil was born and
raised in Buenos Aires, Argentina, where he began his
academic studies. At the age of 20 he transferred to
Hebrew University in Jerusalem, Israel, where he obtained
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