We talk with Mike Hu again about the future of newborn screening and his non-profit, Project GUARDIAN, which stands for Genomic Uniform-Screening Against Rare Diseases In All Newborns. The nonprofit looks to promote genomic sequencing as a platform to newborn screening.
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Stephanie: In our previous
episode, speaking with Dr.
Mike, who we discussed newborn
screening, the way it is currently.
And I would like this opportunity for us
to discuss newborn screening's future.
Now, Mike, you said you were
a founder of a nonprofit.
Would you mind telling us a
little bit more about that?
Mike: Yeah.
And thanks for having me again
and gimme the opportunity to
advertise for our little nonprofit.
So we call our.
Project guardian, which stands for
genomic uniform screening against
rare diseases in all newborns.
Thanks to a friend of
mine to, to to the name.
Stephanie: Yeah, it's
a really creative name.
I like it.
It's very thoughtful acronym
Mike: catchy
Stephanie: Uhhuh.
Very.
So what's the vision of this organization?
Mike: So in a nutshell, we want to
introduce genomic sequencing as a platform
into newborn screening, which enables
us to add a lot of diseases at the same
time to our newborn screening system.
And it enables future diseases to be
added at minimal cost onto the same.
Stephanie: Okay.
So could you tell our listeners
what genome sequencing is
Mike: every one of us have what's
called a set of genome sequences.
So all of our cells have a
set of DNA in the nuclears.
And there are about six.
Codes that made up for the genome.
Every one of our genome
codes are a little different.
But by and large, we
have a high similarity.
It's those minor differences that
determine our eye color, our skin, our
height, our accent, to some extent all of
those things are scripted in the genome.
So when a genetic disease arise, it is,
we call them genomic genetic disease.
It is because their genetic codes
gets modified in some ways, some
of them in a more simplified way we
call them monogenic genetic disease.
Some of them in a more complicated way.
Now with the newborn screening effort,
we're focusing more on the simple.
Mandela diseases where genetic
patterns are clear the ideology,
which means why the diseases
come to present is very clear.
It's linked to single genes.
And how does gene functions
Stephanie: So the Mendelian genetics
that's, taken us back to the punt
square, big, a little a cross it
with big, a little a the little A's
are the recessive trait and the.
Big a is the dominant trade and
NPS, most of them except for hunter
syndrome are the autosomal recessive.
So it's that little, a little a so we're
looking at simple things like that.
What would be some of
the more complex things?
Mike: The co complex things take
on the form of involving multiple
genes and sometimes not just genes.
When we talk about genome sequences,
there are coding sequences where those
sequences are expressed into proteins.
There are non-coding sequences
that works more as a regulator for
the coding sequences, how much.
Translated into protein,
that kind of stuff.
Alright.
So complex genetic diseases.
Most of which we don't have a complete
understanding of unfortunately,
because they're complicated.
They often involve multiple genes.
Each of the genes probably have some
contribution to the presentation
of the symptoms, but it takes
the entirety of those changes to.
The syndrome that we're seeing
and a good example of that.
Certain forms of autism
has genetic traits.
But they are not decided by single genes
that are decided by a multitude of genes.
There's also, what's called
epigenetic modifications.
It's taking us a little bit beyond
the traditional genetic diseases,
but they are genetic modifications,
nonetheless, that are just modified
for that particular person.
Not to the codes, but to how the codes
are translated and trans and expressed
and translated into proteins even.
Stephanie: Okay.
So how does the genomic sequencing,
if you could explain a very simplified
version of how it is different than
mass spectrometry and then how this
would revolutionize our current methods
and standards for newborn screening.
Mike: Yeah.
So first let's give credit.
When credit is due, mass spec
has a working horse for pretty,
for most of our currently.
Newborn screening conditions it's
working fabulously as a platform.
I think it's hard to imagine
something better for screening.
So it has very high sensitivity,
which means if you have a disease.
it most likely can tell it's not
gonna give a lot of false negatives.
Remember we mentioned the last episode,
false negatives are when you have the
condition, but cannot be detected.
So it's not gonna be a lot of that.
It's also very specific in
the sense that when it says.
This sample is positive.
Most likely it is positive.
It doesn't give a lot of false positives.
And so that's the perfect kind of
combination that a public health
screening program needs, cuz you
want to screen because you want to
catch pretty much all the cases.
So you don't want the high, false
negative rate, but at the same time,
because you're screening everyone right.
Base number for that screening
is the entire population.
Which means if you have a slightly
higher, false, positive rate, it is
gonna translate into thousands and
tens of thousands of false positive
patients who needs to be followed up.
Who needs to be tested and so on and
so forth and eventually dismissed
and not just to mention the potential
stress is gonna cause them, it is
gonna be a lot of resources needed
to do the follow up and testing.
And so for a testing platform,
we really want those to
properties for the platform to.
Now, unfortunately, mass spec
is not what do we call almighty?
It depends on the blood
spot to contain some kind of
signature that it can capture.
We call them biomarkers.
So for most of the diseases that
we currently screen for a metabolic
disease will have a fingerprint.
I'd say this kind of . Amal acid
metabolism is going, or you are
gonna have either too much of.
Certain Amal acid or byproduct,
or you're gonna have too
little of it, one or another.
It's gonna cause imbalance in a
system that leads to a disease, right?
For many of the genetic diseases that
we're now talking about, there are no
such fingerprints in the blood spot.
We can get.
The only thing we can get to are the
DNA which can be accurately prepared
and sequenced for, from a block.
Stephanie: right.
Mike: When we talk about expansion of
the newborn screening system, it is
necessary to introduce new platforms.
Goes beyond mass spec and genomic
sequencing is such a suitable one.
Now it's not perfect yet.
The performance of sequencing, there
are a couple of large scale studies
that have been published lately.
And you can see the performance
head to head with MAs spec is not
as great but it comes in two forms.
The first form is I.
Attributed to not having enough data.
Our understanding of genetics
is far from sufficient, right?
So with the accumulation of more
data, a lot of those challenges,
a lot of those performance
characteristics are gonna be improved.
The second one is more complicated.
It's what we call genetic
incomplete penetrance.
So you have.
A certain variant or a
mutation we used to call it.
Now we call it variant.
In certain patients it causes
the disease in certain patients.
It does not
Have to remember we, human beings
are a complex machine that a lot of
genes, a lot of proteins interact
with each other to make us function.
So this actually gets to essentially, I.
In my opinion, in most cases, point
to our incomplete understanding of
those genes or those diseases of those
functions rather than saying this variant
doesn't do what it's supposed to do.
It's because we don't know these might
well be attributed to a polygenic disease.
Remember.
Talked about, there are diseases
that many factors come into play.
Many genes come into play.
This could be one of those cases.
We just don't know those other
genes or other factors yet.
One way or another, I think a, this is
the most available platform that can go
into newborn screening and most promising.
and B with the accumulation of more
data, we can solve most of the problems
that it cannot solve right now.
And C I do think as a public health
screening program, we have a fixed mindset
as to how it should perform and how all
of those conditions or criteria must be
checked off for something to be screened.
I think we should revisit that.
I'm not saying they are absolutely
wrong at what, whatever rate I'm saying
it's worth revisiting so that we can,
for example, tolerate a little bit
of a potentially worse performance.
If there are slightly higher false
positives, do we have enough benefit to
offset whatever consequence that higher.
False positive rate is
causing as a society.
In total, I think there are things we
can tolerate and there are things that
we probably are not ready for, but I
think if we don't even consider it, we
will be missing a lot of opportunities.
Stephanie: So currently right now
in the United Kingdom, they're
piloting a genome sequencing platform
method for their newborn screening.
How would implementing something
like this in the us be different?
Mike: There will be two main differences.
The first difference is in
the UK implementing sequencing
based newborn screen.
their population makeup is a little
bit more uniform than the us, which
means the current database with those
variants a little bit more suitable
for their population compared to
the us now in the us, because we are
really a Hotpod of all kinds of people.
We don't have enough Underrepresented
population's genetic data
represented in the databases yet.
that's a big part of what the
research effort needs to capture.
Now that's one difference.
I think the bigger difference is
how the healthcare systems are
different between the us and the UK.
I'm not a politics expert, in the UK
they have more of a one healthcare system.
Whereas in the us, it's more of
a market based healthcare system.
the us, there are also more layers
of complications such as, the
federal government versus the state
government, the cross border cross
state border care with regard to
insurance coverage, all of those comes
into play when it's newborn screening.
And I think those are the challenges
that are more specific to the us.
Many other countries.
Stephanie: Yeah, just, the same
obstacles that we have currently
with our current method of newborn
screening is that each state is
going to have to independently adopt.
Everything.
So when we were talking about
the variants, I think some of our
listeners are probably familiar
with, the genetic testing.
And when they come back as like
here's a pathogenic variant, here's
a variant of unknown origin, or here
is a variant with no significance.
Could you explain how.
of these results may be
interpreted through sequencing.
Mike: Yeah.
So sequencing is currently being
used in many cases as a secondary
line testing, a confirmatory testing.
If you will, when you have a
biochemical anomaly, you can do
sequencing of the corresponding
genes to confirm what is causing it.
And.
Sometimes you will go
into these rare diseases.
You can sequence the corresponding gene.
You find a variant, but you
don't know what it means because
we haven't seen it before.
It's not captured in the database.
So we call it variants of unknown
significance when it's as a
confirmatory testing method.
it's okay to report more of those,
because what you're trying to find
are clues for someone who is already,
pretty likely affected, because he or
she was discovered by the screening
as a positive, when you move genetic.
Sequencing to first line as a screening
method, this problem needs to take
on a different approach because
we have a lot of parents that we
don't know their significance of.
And so when you are screening,
this is our approach.
We're not going to look into variants
of unknown significance from the get go.
We are going to only look at the
pathogenic and highly likely pathogenic
ones, because you want to make sure you're
not creating too many false positives.
You want to make sure the false,
the positives that you're calling
likely the effective ones.
Now that doesn't mean those variants
of unknown significance cannot be
resolved with the accumulation of
data, especially follow up data.
They can be resolved.
Eventually it just takes
time and accumulation of.
Stephanie: Cause the accuracy
of these tests is really only as
reliable as robust the database.
So the more data we collect,
the more accurate our
interpretation of the results are
Mike: Yeah, exactly.
Stephanie: something this large scale
and this kind of, new technology when.
This is a vision of yours right now.
And the organization that you
founded is looking at advocating
for this genome sequencing as
our method for newborn screening.
What is the timeframe that you
think would be realistic for such
a large scale project like this?
Mike: I think in a nutshell, what
we're looking at on the short end
is a period of five to eight years.
Our mission, in the short term is to
conduct a large scale pilot study in the
realm of, a hundred K to 200 K babies.
And so to enroll that many babies
will take a couple of years.
And then for this type of pilot
study, you need to do a lot of
follow up studies for the positives.
So that you can actually, not only to
confirm because many genetic diseases.
As a baby you just have no
way of confirming, right?
So you have to do follow
ups to confirm you have to
confirm, you have to follow up.
You have to see what the outcome is like
in some cases when it's appropriate see if
the babies are gonna respond in some type
of treatment or experimental treatment.
So collecting all of those follow up
data will take another couple of years.
If we get funded today, I would say
five to eight years, we would have
a good set of data to allow us to
nominate say a hundred to 200 diseases
for the consideration of adding to.
now that would only be the beginning, we
open the door to nominate more diseases,
but, in order for us to tackle the
supposedly more than a thousand genetic
diseases that can be screened for as a
newborn I think it's gonna take a couple
of decades to eventually get there.
Now I do want to say.
being such a large and
long time commitment.
We do have to start somewhere.
This has been a bottleneck, if
you will, to get people excited
because, it's not you can see some
tangible results in two years.
I think everyone wants to have a
short and turnaround, but this is
the kind of thing that we really.
Long term commitment to and have the
patience and commitment to make it.
Stephanie: Thanks, Mike for another
learning opportunity here, I certainly
appreciate your explanation of genome
sequencing and what that could possibly
mean for newborn screenings future.
And so I would like to wish you the
best of luck with your nonprofit
as it forges its way into the
newborn screening landscape.
And thanks again for joining our podcast.
Mike: Thank you very much for inviting me
again, F for all listeners, if you have.
Thoughts about how you might be
able to contribute to such an
effort, feel free to gimme a shout.
Stephanie: Thanks, Mike.