Cracking the Genetic Code – Vandana Shashi
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Cracking the Genetic Code – Vandana Shashi

Shashi: Imagine having a healthy, beautiful child who suddenly falls sick and you have
no idea why. Imagine having a child with medical problems and you’ve sought multiple opinions
and you, yet, don’t have a diagnosis. Imagine staying awake at night because you’re worried
you’re missing out on a treatment for your child, but you have no idea what that treatment
could be. Imagine worrying that your next child could have the same disease, but you
don’t know what the chances are. This is a world that families who have a child
with an undiagnosed or rare disease live in, and it’s not that rare as the term implies.
I can guarantee that every one of you in this room already knows a child who suffers from
a rare and undiagnosed disease. And if you don’t know one personally, you probably are
aware of a child who has it; you just don’t know they have a rare disease.
Till recently we had very little to offer families like this, both in terms of diagnosis
and treatment. Today I’m going to talk to you about a revolutionary new technique that
has allowed us to make diagnosis and treatments in these families. And my goal is, at the
end of the day, you will be able to refer children to institutions like Duke, where
we’re doing work to enhance the lives of these children.
Undiagnosed diseases affect about 30 million Americans. About 8% of babies will be born
who will have an undiagnosed disease at some point in their lifetime. These diseases cause
a huge burden to families, and till recently, as I said, we didn’t know what caused them.
However, what we did know for a while, we surmised that most of these were genetic,
and indeed, over 85% of such diseases are caused by genetic mutations.
To give you a little primer on genes, as you know, genes are made of DNA, and DNA consists
of four letters: A, D, C, and G. And these are arranged in very specific sequences. Each
subsequence [ph] makes up a gene. Every gene makes a protein. And collectively those proteins
determine what we look like, how we grow and develop, how our body functions. And it’s
important to know that having a change, even in one of those letters-and we have about
30 million of these DNA letters spread out across our 20,000 genes-having one letter
switched or missing is enough to cause a devastating disease.
Until recently, we had no way of sifting through all of the data to find that one disease-causing
mutation. Until the herald of whole exome sequencing. Essentially, this technique allows
us to look at all of those 30 million letters to find the one change that could be important
for that particular child. When the first human genome was sequenced, it took about
13 years and cost about $1 billion. Today, because of advancing technology, we can do
it in a matter of weeks, for a couple of thousand dollars.
So I’ve been doing genetics since the dark ages-AKA the ’90s-and I can tell you this
is probably the most exciting advance I’ve had, and I hope to convey some of that excitement
to you. Normally when I see a child in my clinic that-a child who’s suspected to have
a genetic disorder, with traditional methods, and that includes testing for specific single
genes, we can make a diagnosis in about half those children. That’s not the group of children
that I’m talking about when I talk about whole exome sequencing. It’s the remaining half.
That half has rare and undiagnosed diseases, and that’s where whole exome sequencing has
helped resolve a number, and has made a huge difference to these families, as I will tell
you with one of the examples from my clinic. This is Kara [ph]. Kara was doing fine till
she was 15 months old, and she then developed this movement of her eyes, those jerky movements
that you can see in that video. At the same time, it was noted she had difficulty walking.
Many tests were done, but no diagnosis was made in Kara. Simultaneously, it was noticed
that other manifestations were being seen, and over a period of two months, as can be
seen in this video, Kara began to deteriorate. She began to develop paralysis of her upper
arms. As you can see there, she’s having difficulty even holding onto that egg. She developed
a neck tilt, as you can see, because her neck muscles were weak. She started to drool. She
couldn’t swallow. And we were all worried that this was a fatal disease and Kara could
die from it. We needed to intervene, but how? We didn’t have a diagnosis. At this point
we offered whole exome sequencing to her family, and three weeks later, we had an answer, a
diagnosis of a very rare neurological disorder that was caused by mutations within a gene
that was responsible for transportation of vitamin B2, or riboflavin, into her cells.
Now, it’s really important to re-understand that this wasn’t a dietary deficiency. Kara
was getting plenty of B2 in her diet, and indeed, her blood levels were normal. It was
just that she couldn’t transport it into her cells. So we decided we were going to treat
her, and we gave her large doses of B2, about 1,500 times the normal. Her parents were so
desperate for an answer, her mother gave her the first dose in the lobby of our children’s
hospital, and it worked. This is Kara several months-this video was
shot about a year after she was treated, and she’s shown remarkable improvements. As you
can see, she’s now able to lift her arms up, something that she hadn’t been able to do
when the disease was at its peak. She is walking very well. She is now not-having no drooling.
Her nystagmus has improved, and she’s on the way to being a healthy, happy toddler. Not
everything has disappeared. She still has some weakness, but things are much better
and she’s on the road to being a typical child. Taking care of Kara gave me one of the most
exhilarating experience of my life as a physician, and that is when Kara told me she had named
her new doll after me, without being prompted by her parents. [LAUGHTER] What more could
anyone ask for? Not every child has this outcome that Kara
does. All, all of the children that we do are seen at our sequencing clinic. For some
families it’s just a diagnosis, maybe some change in management, but we do all of this
free of cost to the families. The only thing they have to do is come to our clinic.
We are able to do this because of generous support through our dean. Now, we don’t advertise
our clinic. If we did, we would have many referrals. We already have over 400. We’ve
seen about 150, and we’ve made diagnosis in about 40% of those children. Just imagine
if we had more resources. We could certainly help more children like Kara.
In general, whole exome sequencing has been a huge paradigm shift for families who have
a child with an undiagnosed disease. And I cannot tell you enough how much I value this
technology. The important thing that happens at Duke is we don’t give up on any child.
Remember I told you we made a diagnosis in about 40%? Well, we don’t give up on the other
60%. So, for example, the very first 12 patients
that we sequenced we had a diagnosis at first pass on half of those children. But over the
next four years, because we continued to look, we made more diagnoses. And currently we stand
at diagnosis in 11 out of 12 of those initial trio of children that we saw.
So that’s the Duke difference. We never gave up and we never will. Thank you.

One thought on “Cracking the Genetic Code – Vandana Shashi

  1. This is why young people college educated are so stupid and asinine ignorant about life and human history. They'll buy any lie these filthy Animals sell em. They're idea is this. If that professor is a LGBTQ PhD, then they know more than God ever did.Like Romans 1:19-31. Says about the vile and filthy corrupt minded Are!

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