Ep 189 Newborn screening: The future is here

Every year, millions of babies around the world are screened for dozens of treatable conditions within the first day or two of life. What it takes is a few drops of blood on some filter paper, and what it gives is profound: potentially life-saving information. The advent of newborn screening is one of the greatest public achievements of the 20th century; since their earliest implementation, screening programs have diagnosed hundreds of thousands of babies early enough for medical intervention. And the life-saving potential they hold continues to grow with the development of genomic sequencing technology, which will increase the number of screenable conditions by an order of magnitude. In this episode, we explore the serendipitous origins of newborn screening, what the process looks like from a parent’s perspective, and how cutting-edge technology could revolutionize these programs. To help us navigate the exciting future of newborn screening, Dr. Joshua Milner, Professor of Pediatrics and Director of Allergy Immunology and Rheumatology at Columbia University Medical Center joins us to discuss an ambitious research program at NewYork-Presbyterian hospitals titled the GUARDIAN study, or Genomic Uniform-screening Against Rare Disease in All Newborns. Tune in for a truly thrilling episode!

For more on the GUARDIAN study, the groundbreaking research program using genomic sequencing technology to screen newborns at NewYork-Presbyterian hospitals for hundreds of conditions, check out the Advances in Care podcast episode titled “Newborn Gene Sequencing: Expanding Early Detection of Treatable Diseases.”

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Episode Transcript

Speaker 1 (00:00):
Hello. My name is Jessica. My second baby, Max, was
born on my thirty eighth birthday in twenty twenty five.
Max has one older sister, and both of my pregnancies
were pretty normal. Because I was considered to be of
advanced maternal age, we were offered genetic testing each time.
We were able to find out the sex of our
babies very early because of this, and we held our

(00:22):
breath through each round of waiting for the other results. Luckily,
no abnormalities were ever found. I had a scheduled sea
section at thirty nine weeks and I was in the
hospital for four days but doing really well healing and
nursing Max. Doctors, nurses, pediatricians, and lactations specialists were all
in and out of my room from the hospital and

(00:44):
from my own insurance company. I felt like Max and
I were very well taken care of and watched over
during our hospital's stay. On day three, a pediatrician came
into our room and sat down. As soon as she did,
it felt like something was wrong. She began explaining that
Max was given a newborn screening at twenty four hours old.

(01:05):
She explained that newborn screenings are a series of tests
given to babies in order to identify certain metabolic, endocrine,
and hemoglobin disorders. These conditions are serious, but many are
treatable if they are detected early in a child's life.
She told us that Max had tested positive for a
condition called phenyl kitenoria or PKU for short. She explained

(01:31):
that in very rare cases, a person's body cannot process
one specific amino acid that is found in protein. In
these people, the amino acid, phenylalanine, builds up in the
blood and can cause brain damage and severe developmental problems
if the condition is not treated. She told us that
a repeat test would be performed because false positives can occur. However,

(01:55):
she let us know that Max's results were so high
she really didn't need to give that second test to
confidently say he had PKU. She also told us that
she had never seen a newborn screening come back positive
for PKU, and that it was very very rare. My
husband and I both had to be carriers, and any
children we had would then need to receive a recessive

(02:17):
gene from each of us for the disorder to manifest
in them. She asked about our first daughter, who would
have also been given a newborn screening, but we were
not informed about any results with her, so it was
safe to say she did not have PKU. I was
hearing the pediatrician's words and I can reflect back on
them now, but mostly I remember a blur of not

(02:39):
understanding what was going to happen to my baby. Sorry,
I know. I cried for a good amount of time
before finally managing to ask her what life would look
like for Max. The part about protein poisoning his brain
and severe disabilities played on repeat in my mind. Luckily,

(02:59):
for us, PKU is manageable with a very strict diet
and medical formula. I could talk on and on about
our experience with PKU and the low protein world that
I never knew existed before this, but I will stay
focused on newborn screening for this episode. Max just turned
six months old and we are starting to introduce foods.

(03:22):
He gets to eat almost all fruits because they have
very little protein, and a specific list of low protein vegetables.
Eventually he will get to eat some medical foods that
have the fee removed from them, like rice and pasta.
He is closely monitored with weekly heel pricks to test

(03:42):
the level of feet in his blood. By his pediatrician,
who had not encountered PKU since medical school, but has
done an amazing job of research and reaching out to experts,
and by our wonderful genetics team at Emory. Right here
in Atlanta. Max is thriving and hitting every single milestone.

(04:05):
He's even beaten his sister to some because she was
a very late roller. However, absolutely none of this would
have been possible if we had not caught this disorder
as early as we did with a newborn screaming. I
will never be able to express how grateful and privileged
I am to live in a place and in a
time where newborn screaming is the norm. If we were

(04:27):
in another country, or if Max had been born sixty
years ago, his life and ours would look completely different.

Speaker 2 (05:21):
Jessica, thank you, thank you so much for sharing your
story with us. It is so meaningful. I feel like
to hear firsthand the experiences of someone who is like
this information completely changed my life.

Speaker 3 (05:35):
Yeah yeah, it's really truly incredible and powerful and something
that we could never express without your help. So thank
you so much for sharing yours and your family story.
And we're so glad that things are going well.

Speaker 2 (05:48):
Yeah yeah, Hi, I'm Aaron Welsh and I'm Aaron Amman Updike,
and this is this podcast will kill you.

Speaker 3 (05:55):
Welcome to Newborn Screening. To Newborn Screening. I don't know
why I did. And white Hands, I liked that.

Speaker 2 (06:02):
I would like you to do more of that throughout
the rest of our show. Thank you, thank you. I'm
really excited for this episode, Erin, because I feel like
it we talk a lot about individual things that are
you know, individual conditions or medications or organs, gallbladder. But

(06:22):
I feel like this has been a really interesting experience
to learn about a screening, right, not like a diagnostic test,
but like the process of screening and all of the
good and weird and bad and you know, gray areas
that come with it.

Speaker 3 (06:40):
I also am biased, but screening is one of my
favorite things.

Speaker 2 (06:44):
Like, yeah, it's amazing, it's.

Speaker 3 (06:46):
So incredible, and I love it so much, and we'll
get to talk so much about it today. But yeah,
and I love newborn screening specifically, So I'm I'm really
excited about this episode.

Speaker 2 (06:57):
Yes, I'm also excited that we have a very special
guest that we're going to be bringing on later, so
stay tuned. Someone who's like literally an expert on the
ground developing the future. The future is now, and the
future of newborn screening is.

Speaker 3 (07:12):
Now is now and they're doing it. So yeah, kind
of a big deal.

Speaker 2 (07:16):
But we will get to that in a bit.

Speaker 3 (07:18):
First, it is it's quarantiney time.

Speaker 2 (07:21):
It is Aaron. What are we drinking this week?

Speaker 3 (07:23):
We're drinking a drop of knowledge. We are the drop
of blood in that. We don't need to explain it
every time, do we.

Speaker 2 (07:31):
We don't. We'll get to it. It's a drop of blood, yeah, okay, okay,
a drop of knowledge though, like the drink and drink.
I was at a deli the other day and I
saw that, you know, like the I think it's Doctor
Brown's celery soda.

Speaker 3 (07:46):
Yeah, I don't. I don't know what that is, but
I love the idea of it.

Speaker 2 (07:49):
I feel like you would love this. It's so good.
It's celery flavored soda, which sounds weird and maybe not good,
but it's actually delicious. And I thought, what would make
a good cocktail with this? May be a little bit
of a drop of lemon juice and if you would
like some gin.

Speaker 3 (08:05):
If you'd like, if you'd like, why not, we'll post
the full recipe on our website. This podcast willill you.
You know, we actually haven't been posting it on the website.

Speaker 2 (08:13):
I know, I need to figure I don't know how
to do the embedded videos.

Speaker 3 (08:16):
Yeah, I know that it's a simple Google listen. They
they do get posted on all of our social media.
I can't do so.

Speaker 2 (08:24):
Check it out here following us there, but on our website.
Even though we might not yet have Quarantini and plasy
Barta videos up there, we do have lots of other things.
We've got transcripts, We've got links to merch to bookshop
dot org, affiliate page, to our Goodreads list, to music
by Bloodmobile. We've got a contact us form, so if

(08:45):
you have any thoughts or episode suggestions, that's where you
do it. And then we've got a first hand account
form if you have a story of yours that you
would like to share. We probably have other things too,
So check out.

Speaker 3 (08:57):
This podcast would Kill You dot com. While you're on
the in you can also check and make sure that
you are subscribed to the podcatcher that you enjoy or
the exactly Right YouTube channel, where you can also find
video versions of my van a White hands worth It
and that's why we do it, why we do what

(09:18):
we do. The end, Aaron, can you tell us we're
doing this a little out of order? Can you tell
us about the history of newborn screening, because I know
it's a good one.

Speaker 4 (09:31):
It is.

Speaker 2 (09:31):
Yeah, let's take a quick break and I'll tell you
all about it. In the sixty years since the first

(09:54):
newborn screening program began, these screenings have prevented death and
disability in countless children across the globe, making it one
of the greatest public health achievements of the twentieth century,
alongside some of our other favorites like antibiotics, vaccine, fluoride,
and seat belts, which we should do an episode on

(10:16):
seat belts.

Speaker 3 (10:17):
I've never thought of doing an episode on seat belts,
but I bet there's an interesting history there. Eric, Yes, okay,
I'm adding it to the List's like a new episode
that I get to learn about.

Speaker 2 (10:27):
I feel like there will be a lot that you
will tell me about seatbelts.

Speaker 3 (10:30):
I'd have to learn about forces and physics and that
sounds No.

Speaker 2 (10:33):
We don't have to do that, okay, or crash test dummies.

Speaker 3 (10:38):
Anyway, Yeah, okay, anyways, Yeah, going back to newborn screening.

Speaker 2 (10:43):
With one just one drop of blood, we can screen
a newborn baby for dozens of conditions that we can
treat or provide some other medical intervention for.

Speaker 3 (10:54):
It is like more than one actual drop, but like
it's very few drops.

Speaker 2 (10:59):
It's a figurative. It could be one drop if it's
a larger drop. Yeah, anyway, So, but children who end
up receiving a diagnosis for one of these disorders are
now given opportunities that simply were not available at any
other point in human history. Newborn screening has grown steadily

(11:21):
over those past sixty years as our technology allows us
to cast a wider and wider net. In the early
years of newborn screening, you'd find just like one or
two disorders on the panel. Now dozens, There are dozens
soon it could be hundreds and soon meaning like very soon,
like kind of now. For some people, the enormity of

(11:43):
information that is contained in that tiny drop or large drop,
multiple drops, is staggering, and we are just now starting
to realize it's full potential with whole genome sequencing, which
is both excited and overwhelming, because determining whether a disorder

(12:05):
should be included on the panel that can be tricky
to navigate, and it involves weighing things like treatment options,
the feasibility of screening, and the potential benefit to the individual,
among other considerations. And I know that later on we'll
talk more about the Wilson and Younger criteria, right totally,
But going through that process for each and every condition

(12:25):
that we have the ability to screen for, that takes
an enormous amount of time, resources, and combined expertise. But
it is necessary to ensure that we are utilizing newborn
screening to achieve the greatest benefit and equitability Here in
the US. Currently, we have a standardized list of disorders

(12:48):
that all states are recommended to include in their newborn screening.
It's called the Recommended Uniform Screening Panel or our USP,
and it includes thirty eight core and twenty six secondary disorders.
Two main bodies are involved in the decision making process
for the RUSP. There's the Head of HHS and there's

(13:12):
the Advisory Committee Inheritable Disorders in Newborns and Children. Ultimately,
it's up to each state which disorders they screen for,
but all have at least those core ones that I
mentioned on their panel.

Speaker 3 (13:24):
Right, It's like the Recommended minimum, yes, yeah, and that,
but that wasn't always the case, right, So, like before
two thousand.

Speaker 2 (13:32):
And three, which is not that long ago, that is
when the which is when the committee was unofficially formed.
It was later like formalized in two thousand and eight,
but before two thousand and three, some states maybe screen
for just a handful of disorders while others had upwards
of fifty on their list, and so that made newborn
screening like quite uneven across the US. And so since

(13:56):
its creation, one of the major things that the RUSP
has done has been to newborn screening much more equitable
across these states. And it has also provided and especially
vital service as testing technology has advanced so very rapidly
to like a mind boggling degree, right, So, like now
we have whole genome sequencing on the very very near horizon, right,

(14:19):
and we need to be prepared for how to handle
this massive influx of information because if we could incorporate
whole genome sequencing to newborn screening, which spoilers we are doing,
our screening capacity will expand enormously.

Speaker 3 (14:36):
Oh, it totally changes the game.

Speaker 2 (14:38):
Totally, totally. Unfortunately, unfortunately, in April of this year twenty
twenty five, the Department of Health and Human Services, headed
by Robert F. Kennedy Junior, the one and only dissolved
the Advisory Committee on Heritable Disorders in Newborn's and Children.
This is the committee that weighs in on the RUSP. Yeah,

(15:02):
the decision was quietly announced just a few weeks just
a few weeks before the committee was set to evaluate
two new conditions for screening so metachromatic leco dystrophy and
Dusche muscular dystrophy. And so far no formal announcement has
been made regarding whether this committee will be reinstated in
some form or another and if those conditions will be

(15:24):
added to the RUSP, which is hugely disappointing to say
the least, I think for these advocacy groups, the medical
practitioners and researchers who have worked so very hard to
nominate these conditions for inclusion, to get them on the
possible list.

Speaker 3 (15:40):
It's especially just so depressing to think about how so
many of the advocates for every one of these disorders
that ends up being added to the RUSP are parents
of kids whose diagnoses weren't caught because these things are
not on the RUSP, despite the fact that we do
have tests for them and we do have tree it's

(16:00):
available where if things were caught earlier, their condition could
have been different.

Speaker 2 (16:05):
Yep.

Speaker 3 (16:06):
Yeah, So yeah, this is a big deal.

Speaker 2 (16:08):
It is a big deal. It is a big deal,
and you know, I think, just to put some numbers
onto this, every year, approximately thirteen thousand infants in the
US receive a diagnosis for a treatable condition and it
was initially detected through newborn screening.

Speaker 3 (16:24):
Thirteen thousands every year. That's a lot.

Speaker 2 (16:27):
Yeah, and that number has the potential to grow as
we are able to capture more individuals, more.

Speaker 3 (16:34):
Things you add to the list.

Speaker 2 (16:36):
Exactly, especially with genome with whole genome sequencing. But for
that number to grow, for the number of conditions that
we detect to grow, and for newborn screening to grow equitably,
we will need some sort of panel of experts to
help sift through the tsunami of information that is now

(16:56):
available thanks to genomic sequencing. Fortunately, this is like the
hope on the horizon that does seem like it might
be within reach because also in April of this year,
so this is just before the announcement dissolving the Advisory
Committee came out, the NIH Common Fund announced a research

(17:18):
opportunity titled the Newborn Screening by Hold Genome Sequencing Collaboratory Initiative. Okay,
like a lot of words like, yeah, what does that mean?
What does that mean? Yeah, So what it means is
that the NIH has set aside a pot of cash,
so four point eight million dollars per year over three years,
so totally fourteen point four million dollars. Okay, that's what

(17:41):
the NIH has set aside to figure out how we
can incorporate hold genome sequencing into the existing state based
US public health newborn screening programs. So basically, this money
is saying, okay, different programs, please apply to be the
ones to help us, you know, use our existing infrastructure

(18:02):
to develop and implement hold genome sequencing for newborn screening
across the US.

Speaker 3 (18:08):
It's like, help us figure out how we're going to
convert from what we have now to hold genome sequencing
at some point in the future. Yes, and we're going
to do it at these sites that we pick based
on whoever applies to this to.

Speaker 2 (18:21):
This initial collaboratory fund. Yeah, okay, iniative.

Speaker 3 (18:25):
That's great, it's great.

Speaker 2 (18:26):
It's great. So, yeah, the focus of this initiative is
not like, how do we best develop whole genome technolo
hold genome sequencing technology. We have that technology for the
most part, but it's just how can we best fold
it into the screening programs that we already have. So
the the other good news thing about this is that
it's moving pretty rapidly. So applications were due in May

(18:48):
and the earliest start date was September one, twenty twenty five,
so it's possible that by the time this episode is released,
the project is already underway. So that's that's pretty that's
pretty good.

Speaker 5 (18:59):
Right.

Speaker 2 (19:00):
There's still this issue though, of the dissolved advisory committee,
so like what does it mean in light of that?
It does seem that part of this new initiative involves
determining a target gene list, so, in other words, genetic
conditions to include on the screening panel.

Speaker 3 (19:18):
Which is really important and we'll talk in a lot
more detail about how those decisions are made.

Speaker 2 (19:22):
Hugually important, hugely. Yeah, and so this could conceivably supplement
or eventually replace the RUSP as genomics sequencing supplants traditional
newborn screening greatly. Expanding the number of conditions that we
screened for in that process. Okay, and so this project
seems like it would go a long way towards bringing

(19:45):
or it will go a long way towards bringing newborn
screening into this new era of whole genome sequencing. And
the panel that was dissolved would probably have had to
change to incorporate this new technology at.

Speaker 3 (19:59):
Some point the future, once it exists already.

Speaker 2 (20:03):
Right, So that's that's that's the sort of the question
is like, is this a perfect replacement? It doesn't seem
at this point like it is, right, Like I the
questions that I still have are what happens to the
RUSP while this project slash collaboratory gets up and running.
Will those two nominated conditions or or any others that

(20:24):
come up in the you know, in the next few years,
will those be evaluated and added? You know, what happens
if we're still a decade away from genomic sequencing being
the norm at state public health departments like our state's
on their own until then?

Speaker 5 (20:39):
Right?

Speaker 2 (20:39):
What happens? Also after three years when this project ends,
will the funding be renewed?

Speaker 4 (20:48):
I don't know.

Speaker 2 (20:49):
I don't know, So, like I this. I mean, this
initiative is a really exciting and necessary step forward to
meet the informational challenge posed by genomic sequencing technology, because
the future is here, and this project will help us
navigate that future carefully, thoughtfully, and with evidence to support

(21:12):
our decisions. I still don't know what happens to newborn
screening in the meantime.

Speaker 3 (21:17):
Yeah, I feel like that's what sounds very scary about it.
Is it's like, yeah, we're gonna get all ready for this,
but then it's like, so we're just what are we
We're just gonna stay stagnant. Is one state maybe like
advisory board gonna take over like supplant the thing just informally?
I don't know, Like, yeah, is every state just gonna
have to work harder to decide if they're going to

(21:38):
add things to their newborn screening list in the meantime?

Speaker 2 (21:40):
Right, will one state emerge as a leader and say
these are the things that we should be screening for?

Speaker 4 (21:45):
You know?

Speaker 2 (21:46):
Will someone take up that, right torch? I guess yeah? Yeah.
But okay, so now that we know what the future
might look like, even if you still have questions about
the present, shall we take a peek at the past
to see the origins of newborn screening and how far

(22:06):
we've come since then. Yes, let's okay, okay. On November
twenty fifth, nineteen sixty one, a letter to the editor
appeared in Jamma with the title quote blood screening for
fetal keytenuria end quote.

Speaker 3 (22:20):
That's it. That's just the whole title. The whole title. Okay.

Speaker 2 (22:22):
This is a letter to the editor. By the way, So,
in just over six hundred and sixty words, doctor Robert
Guthrie described a new technique for testing newborns for a
condition called feenal keytinuria. Briefly, it's PKU. I won't keep
saying that because it's difficult. Erin, could you give us
like a brief rundown of what PKU is?

Speaker 3 (22:44):
Oh my gosh, really, how on the spot?

Speaker 4 (22:46):
As sure?

Speaker 3 (22:49):
So PKU is as a metabolic disorder where babies are
not able to break down certain amino acids and so
then they build up in their bloodstream and can end
up being toxic.

Speaker 2 (23:02):
That's the shortest way to say it. That's great, okay, perfect,
thank you. I probably should have written something out, but
I was like, no, you did it.

Speaker 3 (23:09):
I have nothing. My heart rate spike.

Speaker 2 (23:12):
Oh no, I'm sorry. It did great, A plus A plus.
So yeah. But this, this test that Robert Gouthrie had
written to the editor about examined a spot of blood
to see if there was an excess amount of an
amino acid called phenylalanine. It was not a diagnostic test,
but it indicated which individuals needed to be tested further

(23:35):
to confirm that they had PKU. The blood screen was
it was inexpensive, it was easy to administer, and it
produced sensitive results. And even better, one of the best things,
the biggest improvements about this test was that it could
be administered twenty four hours after birth, like super early,
super early, because there was an existing PKU test at

(23:57):
this time. But what it did is what it used
urine collected in diapers, and it was only accurate, like
six to eight weeks after birth, during.

Speaker 3 (24:07):
Had time for things to build up probably.

Speaker 2 (24:09):
Yep, exactly, so like enough marker. But then if you're
getting that high enough, like once you were able to
detect there, the baby might have already experienced irreversible brain
damage due to the build up of the semino acids.
So but in the letter, Guthrie mentioned that they had
tested over three thousand kids who were residents at a

(24:30):
state school, two thousand already and this and the test
had confirmed those that had already been diagnosed with the
diaper test and detected at least two more that had
been missed.

Speaker 5 (24:41):
Wow.

Speaker 2 (24:42):
So like this is six hundred and sixty words. He
was able to fit a whole lot.

Speaker 3 (24:47):
Really just creamedeon in there quite concise. Yep, yep.

Speaker 2 (24:51):
And this, this Guthrie test, as it would become known,
it would revolutionize medical genetics and public health because the
potential was immediately seen for like what this could do? Right, So,
in nineteen sixty three, two years after this letter's publication,
Massachusetts became the first state to mandate newborn screening.

Speaker 3 (25:14):
Wow.

Speaker 2 (25:15):
Two years, two years. And this is after successful campaigning
by the Joseph P. Kennedy Junior Foundation and JFK's New
Task Force. Other states and countries shortly followed Massachusetts lead,
and by nineteen sixty five, thirty two US states had
laws for newborn screening.

Speaker 3 (25:34):
Wow.

Speaker 2 (25:35):
Four years, that's very fast.

Speaker 3 (25:37):
Yeah, in medical times.

Speaker 2 (25:39):
In medical I mean, right. And so of those thirty
two US states that had you know, included newborn screening,
twenty seven had mandated it okay, And as the number
of babies whose blood was tested climbed into the hundreds
of thousands, and then into the millions, it was clear
that newborn screening was not only FEASA, it was changing

(26:01):
people's lives and futures. And so people were like, well,
what else can we do with this? Like this has
had such a hugely positive impact so far, there must
be more out there that we can screen for, And
so researchers were looking into other conditions that could be
treated early and that could be easily included in this

(26:22):
blood drop, this heel prick test, And by the nineteen
sixties the late nineteen sixties, a few other conditions ended
up being added to some country screening protocols, and research
was still underway to identify others, as it will always
be underway. And so along with this heightened interest in
this area of research came this realization that, like okay,

(26:44):
we have to figure out some ethical guidelines for what
we should and what we shouldn't screen for, Like how
should we prioritize research efforts to achieve the greatest benefit
while also minimizing the potential for harm. Because knowledge, yes,
knowledge can be power if we use that knowledge for good,

(27:04):
if an early diagnosis, you know, allows us to intervene
and prevent a disease from progressing further, or if it
helps us to better look out for signs of disease later,
like if we know that, oh, we should keep an
eye out for this, right, But knowledge also has the
power to harm. Sometimes it may be better not to know,

(27:26):
especially if knowing doesn't change anything. If you get if
you test positive for something and there are no available treatments,
what happens? What do you do? What does that knowledge
give you? And that's like, I mean, there's this is
like a whole field medical medical philosophy.

Speaker 3 (27:43):
Yes, yeah, and it's all a very individual It's really
it's an individual right to know or not to know
at the bottom of line, right, yeah, right.

Speaker 2 (27:53):
And so with all of the sort of these ethical
questions swirling around newborn screening, in nineteen sixty eight, the
WHO published a report in which they outlined ten principles
for which disorders should be included in newborn screening programs.
And this is the so called Wilson and Younger criteria,
which I know you'll go into a bit more depth

(28:13):
with this erin but A couple of the key points
include that a condition can be tested for, like we
have a suitable test that will, you know, help to
not detect it. It's not diagnostic, but like, yeah, I
don't know why I can't find the words, but you
know what I mean, right.

Speaker 3 (28:31):
You've got to be able to check for it.

Speaker 2 (28:33):
You got to be able to check for it. And
it sounds fairly straightforward.

Speaker 3 (28:36):
But yeah.

Speaker 2 (28:37):
And then also the treatment exists, like some sort of
medical intervention exists. And in the decades since these criteria
were put forth, they've stayed quite relevant and helpful, but
it's not always as clear cut as you think. Okay,
a treatment exists. Check, Okay, this a screening test exists.
Chat check exactly right, Like, there's a lot more there's

(29:01):
a lot more new there's a lot more gray area.
And so as technology especially has expanded our capabilities to
detect a wider and wider array of conditions, these these
gray areas, this nuance has really grown with that newborn
screening is not without controversy and the harm benefit calculation
is not always clear cut. So let's get into some

(29:22):
newborn screening nuance. Okay, every history of newborn screening starts
with Guthrie and PKU, and I think it's worth asking
why PKU, and to some extent why Guthrie like, who
was this guy? Yeah, I'll tell your I mean, aren't

(29:45):
we all yes, we can all yeah. Uh. PKU had
only been described a couple of decades before Guthrie developed
his test, so it's like actually fairly recent in Guthrie's time,
and had been described by an Norwegian pediatrics resident in
nineteen thirty four. So this guy Falling examined a couple
of siblings who were both intellectually disabled, and he unexpectedly

(30:09):
found a dietary derivative of phenolalitin in their urine, something
that he had never been described before. Just he was like,
there's surely this is someone has had to have written
about this.

Speaker 3 (30:20):
Nope.

Speaker 2 (30:22):
So he wrote it up and was like, I think
that this might be linked to the intellectual disability in
these children, and if you are. Other physicians were like, okay,
well we'll take a peek too, and they confirmed this
finding in other children who also had intellectual disabilities, and
so it was like, Okay, this is a stronger, stronger
evidence for these two things being Linkedah, could the intellectual

(30:45):
disability that we have observed be caused by a buildup
of phenolalanine in the brain, and if so, could it
be prevented through a diet that restricted phenolalanine, because that
is that was possible. It's not like something that you
were always constantly exposed to. Some foods have it, some

(31:06):
foods don't, and so.

Speaker 3 (31:08):
And it's not something that like your body is just
making willing nilly. It's like you are consuming it and
you're not able to break it down in the way
that you're supposed to, and therefore it builds up two
toxic levels.

Speaker 2 (31:19):
So if you are just.

Speaker 3 (31:19):
Never exposed to it, if you never consume it, then
you can maintain low.

Speaker 2 (31:23):
Level exactly exactly. And so that is that logic right
there is exactly what a couple of British doctors used
to create or propose this phenolalanine restricted diet. And so
they were like, if we administered this early enough, what
is it possible to prevent the intellectual disability and some
of the other symptoms associated with PKUM. So they're like, well,

(31:45):
let's try it out.

Speaker 3 (31:46):
Yeah.

Speaker 2 (31:47):
The issue, though, which is what I said earlier, was
that phenolalanine sometimes took a few weeks to show up
in the urine, at which point the child's brain made
might already have been damaged. And so the ad event
of Guthrie's test was faster. Test was huge. Within twenty
four hours, you could say, oh, yes, there is like
we need to implement a pheeninality restricted diet. But Guthrie,

(32:12):
Guthrie himself came from kind of an unusual background. He
was not involved, He had no background in metabolic disorders
or genetic conditions. He was a microbiologist by training, okay,
and he had been doing cancer research before he developed
this test, So like, how how did he go from
point A to point B? Well, Gothrie happened to also

(32:35):
have a son who was intellectually disabled, and he was
involved in the local chapter of what was then called
the Association for Retarded Children, now called the ARC, and
this is where he learned about PKU and the newly
developed diet. He was talking I think to a speaker
who had come and was discussing this, and he was
like but at the same time, I think he had

(32:56):
heard about the limitations of the test and was like, gosh,
we could really do something. If we could have a
faster test, that could be huge. Maybe there's a better way.
And so he was at the time working on a
bacterial inhibition essay for cancer screening, and he was like,
what if I just tweaked a few things here and

(33:17):
there and used the same thing to look for funlalanine
And that's what he did. He like that was like
so much, here's my idea, and here it is. It worked.

Speaker 3 (33:29):
I love stories like that where it's like, oh, I
was working on this other thing, but I was like, huh,
I wonder if I could do it for this thing,
and then bing bang boom, and now you've like revolutionized
people's lives people's lives.

Speaker 2 (33:41):
And I think it also just like goes to show
sometimes that thinking outside the box, like approaching a problem
as an outsider, can really open up your perspective and
be like oh and everyone else is like, oh my god,
the solution was there all along. I mean, I think
I might be overstating this simplicity of it and like

(34:01):
the work that he put into it, but still I
think it was like a flash of insight. Yeah, And
so he actually left his cancer work and took on
a job at a Children's Hospital to continue his research
on this.

Speaker 3 (34:15):
Wow, I know.

Speaker 2 (34:17):
And so in the midst of this work, prior to
his letter to the editor, he learned also that his niece,
who was severely intellectually disabled, had been diagnosed with PKU,
and so that gave him even more like motivation inspiration
knowing that this test could be critical in delivering time
sensitive information that could prevent the effects of PKU. Yeah.

(34:41):
So when he announced his test in nineteen sixty one,
it was mostly though not entirely enthusiastically.

Speaker 3 (34:47):
Received sounds about right, yeah.

Speaker 2 (34:50):
I mean that's I feel like a like a normal reaction.

Speaker 3 (34:53):
Right, better than most I would say.

Speaker 2 (34:55):
Yeah, this was a sensitive test that could help with
a diagnosis for a condition that had a very clear
and effective intervention if administered immediately, a phenilalanine restricted diet.
But some people, including a prominent doctor, remained vocal skeptics,
saying things like oh, well, I don't think it's felinilalanine

(35:18):
that causes brain damage, or saying like well, I don't
think the diet is effective, or it might be effective
and only a few and so this like led to
concern that this was a costly diet that could harm
or bother those who didn't need it, and also it
was just like, why are you going through the effort
of this if it's not going to provide a benefit.

Speaker 3 (35:38):
They were like, we don't feel like you know PKU
well enough.

Speaker 2 (35:42):
Yes, I think that was one of the concerns. Or
it was like this might be effective in some children
with PKU, but not everyone, like this is not yeah
right right, And a couple of the other complaints that
were less medically focused. One was that newborn screening with socialism,

(36:04):
you know, the boogeyman, and also that I found this
one really interesting, actually that newborn screening would take focus
away from social support programs for children with intellectual disabilities.

Speaker 3 (36:17):
That is an interesting critique.

Speaker 2 (36:18):
Yeah, I see where they're coming from with that, because
if it's like, if we have a limited pot of
money and we're now spending it on research rather than
social safety like social safety net programs, then you know.

Speaker 3 (36:30):
You're going to take our money and you're going to
shunt it over there, right, rather than yeah, yeah, yeah,
I get that.

Speaker 2 (36:35):
I don't know if that is actually what, like, was
the pot of money the same right, was it the
same source? But this was also especially felt, I think
because kids with PKU made up a very small proportion
of all kids who had intellectual or developmental disabilities. And finally,
the last complaint was that the test was not accurate

(36:57):
enough or not specific enough, so meaning it either missed
kids who had PKU or it led to false positives. Okay,
false positives.

Speaker 3 (37:05):
We'll talk all about things like that, Aaron, Yeah, we will.

Speaker 2 (37:09):
Many of these objections faded away over the years as
the test improved and as more data were collected on
the efficacy of early intervention, but some objections remained, not
just for PKU, but for other conditions newly added or
proposed to be added to newborn screening programs. Because, especially

(37:31):
as technology has allowed us to cast a wider net,
first with the incorporation of tandem mass spectrometry in the
nineteen nineties and now with whole genome sequencing capabilities, one
major area that people have expressed concern about is privacy.
How to ensure that our genetic information cannot be used

(37:53):
without our consent, for instance, by insurance companies to discriminate
against us. Right, I think that's a valid concerned Totally,
Every newborn screening program has privacy policies intended to protect
against this, and clear guidelines on how the information will
be used, including restricting who can access it. Whether that's

(38:16):
enough is beyond the scope of this conversation, and I
think that like a legal podcast should definitely pick that up.
I'd be fascinated to tune into that. And I also
want to make sure that we I talk about the
other considerations for newborn screening. The first is what happens
if a positive test ultimately leads to a confirmed diagnosis? Right,

(38:41):
The path forward is not always clear when it comes
to treatment, you know, I think that earlier we kind
of touched on this when in the criteria where we're
like is there treatment right, yes or no?

Speaker 5 (38:51):
Right?

Speaker 2 (38:52):
Sometimes that answer is not obvious. So, like many of
the conditions that are included in newborn screening have a
range of severe and since these are rare disorders, we
might not have as much data as we like for
how effective some of these treatments or interventions are, especially
in the long term. Sometimes deciding what to do, you know,

(39:14):
should I do this treatment or that one? Should I
do one at all? Sometimes that's not clear cut. Diagnoses
can be inconclusive or intermediary. So for example, cystic fibrosis,
sometimes it's like we don't know the severity based on
whichever specific illeal we're data deficient in some of these situation.

Speaker 3 (39:33):
We have great treatments for this type and less great
treatments for this type. So there's still so many questions
wor yes, yeah.

Speaker 2 (39:43):
And this could leave parents to wonder, you know, if
my child may never show symptoms, what should I be
doing here?

Speaker 3 (39:51):
Right?

Speaker 2 (39:51):
And this is something absolutely that is taken into account
when considering whether a condition should be included in the screening.

Speaker 3 (39:58):
It's almost like that's why we need people who know
what they're doing to make the decisions about what we
should include on the panel.

Speaker 2 (40:05):
Yes, yes, but we are also though, approaching an era
where someone's entire genetic information could be accessed by or
provided to parents. Yep, who does that information belong to?
Yeap the child the parents are both like should parents
be able to ask for all results even if there

(40:26):
are no interventions or treatments?

Speaker 4 (40:29):
Right?

Speaker 2 (40:29):
Knowledge can weigh heavily.

Speaker 3 (40:31):
Or things that might not happen until adulthood, or maybe
you're at higher risk of something as an adult but
not as a child, Like what.

Speaker 2 (40:40):
What is a parent allowed access to that right, and
so currently these are largely hypothetical concerns. We haven't quite
gotten to that point with sequencing, but it's conceivable that
we will have to confront them eventually.

Speaker 3 (40:54):
And then.

Speaker 2 (40:56):
There's the other scenario, what happens if a positive test
positive screening test does not lead to a confirmed diagnosis,
and this is very often the case. The high rates
of false positives in newborn screening are a side effect
of wanting to make sure that we catch every true positive,
right that is, that is often how screenings go, and

(41:17):
it is a it's not unique to newborn screening, and
newborn screening is just that it is a screening. It
screens for certain conditions. It's not diagnostic at all. So
if someone's newborn screening is flagged for a certain condition,
that that baby will undergo additional tests to confirm or

(41:37):
reject the diagnosis, and the vast majority of the time,
like I mentioned, it ends up being a false positive.
But that doesn't like, that doesn't undo the financial cost
of the additional testing, battling with insurance, and the enormous
emotional turmoil experienced by parents during those weeks of not
knowing or imagining the worst. One study also found that

(42:00):
most doctors do not discuss newborn screening with parents before
the birth. And I know that we'll tell you. There's
like that, I know, and many, whether it's pediatricians or OB's,
feel ill equipped to explain it. And then that's the
other sort of question is like, are you getting your
care from your OB? Is your who should tell you
about newborn screening?

Speaker 3 (42:19):
Maybe you should have a family medicine doctor.

Speaker 2 (42:21):
I'm totally biased, but if you don't have a family
medicine doctor, is your OB going to tell you? Is
your pediatrician going to tell you? Are you going to
see your pediatrician before you give nor?

Speaker 3 (42:33):
Usually not exactly. So no, it's a total It is
a failure of the way that our system is set up.
Is that yeah, A, there's usually not time in OBI visits,
No one gets enough time in those, and B you're
not probably talking about newborn stuff in your OB visits
right right, And then at your pediatrician visit it's already done.
So you get like you're in the hospital, you just

(42:53):
delivered a baby, and a nurse comes in and is like, okay,
we're going to do the screening or a resident comes
in and it's like, okay, we're going to do the
screening and you're like, oh, all what or you don't even.

Speaker 2 (43:02):
Know that it's happening. I asked my mom. I was like,
do you remember, and she goes, oh did did did
that happen? I was like, yes, it did, it did.
We were all of us like it's mandatory, so it's
it is a This is something that I think that
that lack of communication can leave parents terrified and in
the dark seeking information from doctor Google that could scare

(43:26):
them even further. Right, newborn screening saves lives and has
had a tremendously positive impact over the past sixty plus years,
but these positives can make it easier to brush aside
the negatives, which can be substantial for some you know
better testing that reduces the false positive rate would go

(43:47):
a long way toward alleviating some of the anxiety and fear.
Not to mention the cost of additional testing and having
access to genetic counseling can be hugely beneficial. Information not
just about the initial counseling, additional testing, or what positive
result might mean, but also what the options are if

(44:08):
a diagnosis ends up being made. Genetic counseling is a
tremendous field. We should we should talk more about it.

Speaker 3 (44:15):
We should be we need more genetic counselors.

Speaker 2 (44:18):
Yes, because unfortunately not everyone has access to a genetic counselor, so.

Speaker 3 (44:23):
They cannot like standard.

Speaker 2 (44:25):
Not it's not and so it's really easy then to
get overwhelmed by the vast amount of information and misinformation
out there. So again, newborn screening, though has saved the
lives and improved the health of countless newborns around the globe,
it is not perfect. There is room for improvement, you know,
opportunities to reduce some of the harm and false positives,

(44:47):
remove the uncertainty and what to do next for true positives,
and better communicate to all parents what the screening does.
But if we want to make any advancements in these areas,
we need more investment in research, communication programs, and a
better healthcare system overall to make sure that this powerful
knowledge can continue to make a positive impact.

Speaker 3 (45:08):
You're saying we should invest in public health there.

Speaker 2 (45:10):
Always, I will never stop saying it, except now when
I turn it over to you to tell me more
about how newborn screening works.

Speaker 3 (45:19):
So then I can say it.

Speaker 2 (45:20):
Yes, that's your truth.

Speaker 3 (45:22):
I can't wait erin thank you. That was such a
good setup. I love screening so much. I want to

(45:47):
talk for just a minute about, like what is the
concept of screening because we've never gotten to on this
podcast before really, So, the concept of screening means that
we are testing a symptomatic people like entire usually hopefully
well defined populations of people. So in the case of
newborn screening, we're talking about testing every single newborn for

(46:11):
a disease or a disorder, or a suite of them,
before they show any symptoms. And in medicine, we screen
for so many things, like we screen everyone with a
cervix for cervical cancer starting at age twenty one or
twenty five. We screen every adult over forty five for
colon cancer or earlier, depending on your family history. We
screen for high blood pressure. You might not even know

(46:31):
that's what we're doing. We're screening for high cholesterol, diabetes,
breast cancer.

Speaker 4 (46:34):
Right.

Speaker 3 (46:35):
We are looking for evidence of a disease before you
ever show any signs or symptoms of that disease, right right,
So in newborn screening, we are testing all of these
babies right after delivery, usually within the first twenty four
to forty eight hours of life for a whole suite
of disorders that they may develop later in their life.

(47:01):
And all screening, but especially newborn screening because of the
scale on which it's done, is a process, not an event,
right it is.

Speaker 2 (47:11):
Yes, I love that process, not an event.

Speaker 3 (47:14):
And that process is dependent on a system that has
a lot of different pieces that have to be in place.
It has to start with our federal and state public
health agencies deciding as a group, based on expertise, what
they're screening for yep. And then there are both hospital
based exams which a lot of people might not realize

(47:36):
are even happening, like a hearing test and a congenital
heart disease screen, as well as the blood test or
the heel prick test, which that test has to then
be shipped and analyzed in a systematic way. And then
there's all of the stuff that has to happen after
that test. The results have to be reported to the

(47:56):
families and the healthcare system in which they're a part of.
There's then follow up diagnostic testing that has to be
coordinated and completed. There's all these additional appointments hopefully you
have access to genetic counseling, there might be parental testing,
and then there is some kind of treatment or intervention
in order to prevent the harms of that condition for

(48:17):
which we screened.

Speaker 2 (48:18):
Right, that's a lot, it's a lot.

Speaker 3 (48:21):
It's not a small event. No, no, no, And like
I had mentioned, we think of the newborn screening test
as just that blood spot test, the heel prick, but
it is a lot more than that. There's like physical
exam testing that is done on every single baby to
look for evidence of certain conditions. There's the congenital heart disease,

(48:41):
there's the hearing test. But the blood test is what
we're going to focus on for this episode. And in
that what they do, if anyone hasn't seen this happen before,
they take a little teeny tiny lancet like you would
use to check your blood glucose and they prick the
back of the baby's heel, usually after you warm it
up really good so that you've got good blood flow,

(49:03):
and then you drop this blood onto a little filter paper.
There's just these little circles. It's not like a whole vial.
It's literally just like dropping it onto this paper. In
these little circles that you fill up and then you
let it dry and you mail it to your public
health department, who usually is the ones who do the screening.
And you had mentioned, Aaron, the different modalities today, we
use a bunch of different modalities actually for our blood

(49:24):
screening tests. A lot of them use mass spectrometry, some
of them might use hemoglobe and electrophoresis, and then there
are some genetic tests as well. It all just depends
on what you're screening for, right, Yeah, And all of
this screening generally happens at right around twenty four hours
of life.

Speaker 2 (49:43):
It's a lot of information all at once, and it's
just still you don't you might not even know that
it's happening exactly exactly.

Speaker 3 (49:51):
And I'm not going to give you a list. I'm
not going to go through like every single condition that
we test for in the US and around the globe
is not one single test. And you kind of walked
us through, Aaron, how this all got started. But it
was after the introduction of mass spectrometry that things really
kind of ramped up. But every single state in the

(50:15):
US manages its newborn screening program a little bit differently
and has slightly different things that they have on their
blood tests. So some states test for a lot more
conditions and some states really just rely on that recommended
Universal Screening protocol that they use to make their list essentially,

(50:36):
and all of that is now in question. Many of
the conditions that we screen for on this blood test
are what we call metabolic disorders like PKU, which means
that they are disorders in the way that our bodies
process foods or other things that can end up leading
to the accumulation of toxic byproducts or sometimes deficiencies in

(50:59):
other acids or things like that. There are really wide
range of these metabolic conditions that we can test for.
It there's a lot of them on newborn screening protocols.
But there's also disorders of hemoglobin right like zickle cell
anemia is on most of the newborn screenings. There's diseases
of the immune system, especially if they're caused by known

(51:20):
genetic mutations like SKID for example, or severe combined immune deficiency.
There's things like cystic fibrosis, can general hypothyroidism, and most
across the board, these disorders without treatment, without identification and
treatment can cause really significant impacts on growth. And development

(51:43):
and in many cases can result in life threatening complications
very early in life, in infancy and in childhood. And
many of them have relatively straightforward treatments as far as
all things in medicine go, right, like special formulas, avoidance
of certain foods. Sometimes it's additional therapies or immanizations. Some

(52:06):
might be more involved, For example, with SKID, it might
be something like a bone marrow transplant, which is very
involved and not a decision to be taken lightly, but
potentially allows for cure of a disease.

Speaker 2 (52:19):
Right, yeah, curative, it's amazing. Yeah.

Speaker 3 (52:22):
Yeah. And so whenever we are talking about screening tests,
not just newborn screening but all of the screening tests
that we do in medicine, there are, like you mentioned,
a lot of factors that we have to consider to
decide what populations we're screening and what types of things
we're screening for, and what types of tests we should
use for that screening. So it was Wilson and Younger

(52:45):
you mentioned who came up with this list of ten
criteria back in the sixties, nineteen sixty eight. Yeah, yea,
and those mostly hold up over time, like they're mostly
the same. But I did find a more recent paper
from twenty eleven that what I liked is that they
really tried to take into account how much some of
these ideas that we think of are going to have

(53:07):
to change as we advance into genetic testing. Right, so
there is a bit more of like an intensive framework
about how to decide what we're screening for and how
we're screening it.

Speaker 2 (53:20):
I think it's like it comes down to what is
the how how much does this predict? How well does
this allele this variant genetic variant predict a disease versus predisposed.

Speaker 3 (53:33):
Exactly exactly right. There's a lot of there's a lot
of things that you have to consider, especially as you
get into that genetic testing framework. But you kind of
mentioned some of the biggest ones, and I want to
just reiterate them, I think because they're so important. Like
I guess what I'm trying to emphasize is how what
is being screened for is not a flippant decision.

Speaker 2 (53:55):
No no, no, it's not like, hey, you know what,
we've got the capacity to do all of this, Let's
just do it all.

Speaker 3 (54:00):
Right, Let's just check everyone for everything. Like That's not
how it's done.

Speaker 2 (54:03):
And I think that, like the the other piece of
the puzzle too, is like this, there has to be
individual benefit. You think, Okay, well, but if we if
we don't currently have a treatment for this condition, but
we if we screen for tested, than we could in
the future if we if we know that these kids
have it. But like that's not again, that's not what

(54:26):
individual benefit is this kid getting if there is no
existing treatment.

Speaker 3 (54:30):
Exactly so exactly so some of like big picture, the
biggest things that we have to have in place for
a disorder to be like added to a screening list.
We have to have a test that is appropriate for
the condition that we're looking for, okay, and for screening purposes.
What that means is that we have to have something

(54:50):
that has what you mentioned aaron a high sensitivity, which
means that we want it to pick up as many
cases as possible. We don't want anyone to be missed
and have a a bunch of false negatives, because that
means we are falsely reassuring people that you do not
have this condition if we don't have a highly sensitive test.
But the flip side of that is often, though not always,

(55:12):
that screening tests can then have false positives, right, which
then means that we have to have additional testing that
exists that's really good and very specific to confirm a
diagnosis if something is picked up on these screening tests, right.
And how good a test does, like how well it

(55:33):
actually performs, usually depends on how prevalent or how rare
a disease is in the population. So we also have
to consider some of the factors of the conditions themselves.
Are they an individual health problem and are they a
public health problem. We have to know can we do
something to prevent them if we identify them early, because,

(55:53):
like you said, it is not considered ethical to screen
for something that we can't do anything about. So we
have to know that these conditions exist. We can't screen
for things that we don't know about yet. And they
have to have some kind of asymptomatic stage where this
screening can be completed. And then we have to have
some kind of treatment or intervention to offer something that

(56:14):
can actually reasonably be accessed by everyone who you're screening, right.
And then, because this is public health, there's also always
a cost consideration, right, Like we are going to tell
you that public health investment always saves money because it
does always, but the public health agencies also are going
to be doing this cost analysis and then like they

(56:35):
have to weigh what is the cost of screening the
entire population plus the cost of the testing for both
false positives and true positives weighed against the potential savings
in medical care if we catch and treat these disease
early and either cure them or prevent severe disease down
the line. So all of this has to be considered
when we are deciding what conditions have to be on

(56:55):
this list to screen for or not. You need a
lot of expertise and you need a lot of data, yes, yeah,
And this list has been consistently updated over time as
we've developed better testing or developed better treatments. A really
good example of this is spinal muscular atrophy or SMA.

(57:15):
Yeah yeah, This a treatment got approved in twenty sixteen,
and before that we didn't have any treatment available for
this disorder, which can be very, very detrimental. And because
we now had a new treatment as of twenty sixteen,
people started lobbying and recommending that this get added to
the list of recommended universal screening, and it was added

(57:37):
in twenty eighteen. It's still not on every individual states list,
but it is on the RUSP.

Speaker 2 (57:43):
Yeah, it's amazing, Like I feel like that has been
newborn screening has grown so substantially. Yeah, and like consistently,
well not even consistently exponentially over the years, right, And
it's evidence based.

Speaker 3 (57:57):
Maybe we have these.

Speaker 2 (57:59):
Criteria, we have reasons to include these conditions.

Speaker 3 (58:03):
Yeah, yeah, and all of that will change with the
advent of genomic sequencing, right, yes, without a doubt. Yeah,
genomic sequencing. Whole genome sequencing will and is enabling screening
for a much wider range of conditions, but without substantial

(58:28):
additional costs. Because right now, every single disorder, we have
to make sure that we have a test, that that
test is cost effective and like a good enough test,
and then we have to decide based on the treatments
and all of those other things, do we add it
to this list? Can people have the capacity to add
this test to their public health department? But with this

(58:49):
switch to genomic sequencing, like the game is totally changed.
And literally every recent paper in the last like five
years that has been written about newborn screening is about
genomics and the and this future is here. Like you said,
the UK has actually already made a commitment to switching
all of their newborn screening to genomics within the next
ten years. So exciting this is happening. There is no

(59:12):
going back, And like I said, in contrast to now,
we won't need to do all of these different types
of tests. By sequencing the entire genome of an individual,
we can look for so many different diseases and disorders.
As long as there is an identifiable gene associated with
this condition, you could, at least in theory, add it

(59:35):
to the list of genes that you're looking for. But
those same conditions and questions that we have mentioned will
also apply when we are talking about using genomics. Right,
these conditions need to be identifiable, they have to have
an asymptomatic stage. We should have some kind of treatment
or intervention. Right, you have to have confirmatory diagnostic testing.

(59:58):
And then, like you said, there's all of these additional
questions that come with genomics, like what about all of
these genes where we know there's an increased risk of
disease but maybe not necessarily a disease. What about all
of the rest of the data that comes by sequencing
an entire genome. Who owns it? Who protects it? Who
else is going to have access to that information? Do

(01:00:20):
they want to know this information?

Speaker 2 (01:00:22):
How long does is it kept? How you know, like
can it be reaccessed exactly if you want? You know,
what's for what purposes? And so this comes with a
lot of complications and a lot of potential for huge benefit.
So we brought in an expert so then we don't
have to tell you all about it the best part.

Speaker 3 (01:00:44):
Yes, that's right. We brought in one of the researchers
who is involved in this huge project here in the
US which is very exciting called the Guardian Study, which
has already begun, like it's already well underway. It has
been screening really large numbers of babies in New York
City using genomics tools. The Guardian Study has been it's
been recruiting, it still is recruiting families with newborns at

(01:01:06):
New York Presbyterian Hospitals for over two hundred genes associated
with specific conditions known to affect young children. Two hundred
I know, from thirty eight to two hundred. Yeah, like
the highest at least that I could find. I think
the highest state is California with like seventy five or
so conditions that are on our screening test. So this

(01:01:26):
is like X or so much bigger yep. And some
of these conditions that they're screening for are incredibly rare
and they have had really interesting and important results already. Aarin,
your other podcast that you host, Advances and Care, had
a really excellent episode on the Guardian study. So can
you introduce us to our interviewee.

Speaker 2 (01:01:48):
I am thrilled to yes. In that episode of Advances
and Care, which was called Newborn Gene Sequencing Expanding early
Detection of treatable Diseases, it's a great episode in March,
a good episode, the production team everyone out, all the
physician scientists amazing, just really really cool. But one of
the physician scientists featured in that episode was a one

(01:02:12):
doctor Josh Milner, who is Professor of Pediatrics and director
of Allergy, Immunology and Rheumatology at Columbia University Medical Center,
who was involved in the Guardian study. And so yes,
we're we got to speak with with doctor Milner about
the Guardian study and about all of these different aspects
of WHLD genome sequencing and what that could mean. And

(01:02:34):
also doctor Milner is part of a group of immunologists
who is working to make genomic sequencing a reality for
newborn screenings across the country.

Speaker 3 (01:02:44):
And his role.

Speaker 2 (01:02:45):
One of his roles involves making recommendations for which conditions
to include on screening panels, and he is extremely enthusiastic
about the recent efforts in the UK that you mentioned,
Aaron to incorporate genomic sequencing into newborn screening and also
that new NIH initiative that I mentioned at the top. Yeah,
and so in our interview, doctor Milner shares some really

(01:03:06):
fascinating insights about the potential offered by genomic sequencing for
newborn screening and we are so excited to bring these
to you.

Speaker 3 (01:03:16):
Let's go to the interview erin.

Speaker 2 (01:03:20):
Doctor Milner, thank you so much for joining us today.

Speaker 3 (01:03:23):
Thank you. We're thrilled.

Speaker 4 (01:03:24):
It's a pleasure.

Speaker 2 (01:03:26):
So so far in this episode, we've discussed how standard
newborn screening works as well as the history of its development,
and we are really thrilled to hear from you about
what the future might hold for this important screening process,
especially with the application of genome sequencing. Could you give
us an overview of the Guardian study and how it's

(01:03:47):
different from standard newborn screening approaches.

Speaker 4 (01:03:50):
So basically the idea of the Guardian study and generally
speaking doing genomic newborn screening is that when that blood
spot is taken from the heel, usually of a newborn baby,
that the DNA be extracted and sent for sequencing for

(01:04:16):
genes that might impact health. It's still the same sample
and it's the same process of sending it off to screen.
But when you do something like whole genome sequencing, where
you're getting the genetic code for the entire person, you
actually can look for many many more disorders where if

(01:04:41):
you have a what we call a variation which used
to be called a mutation in a particular gene that
is known to cause a disease, that that can actually
be ascertained within the first few weeks of life. And
what everyone does is essentially picks only genes where if

(01:05:04):
you found a variation in that gene that there would
be something you could do about it to prevent or
cure the disease. And so there are hundreds and hundreds
of such genes on our list, and it's a constantly
evolving process of can we now there's something to do

(01:05:26):
for this particular disorder, Oh, now we know, actually this
is a new genetic problem, but it already comes with
something you could do about it. And then, at least
in the study the way that it's been done right now,
some of the genes do encode for the problem that
you might pick up with the regular newborn screen that
we already have, so those can be compared to make

(01:05:48):
sure that the genetic strategy does not miss anything. But
it also can actually even help clarify where you're like, well,
I'm not sure why this particular problem came up on
the regular newborn screen, but the genetic testing told me
exactly what it was. More often than not, though, the
genetic testing finds something that couldn't be tested with the

(01:06:11):
regular newborn screen. The thing about the genetic testing is
every time you make a list of the genes that
you want to be screening for mutations or variations, it
doesn't cost anymore. It's just, you know, it's the same analysis.
Whereas with the regular newborn screening, every single new disease

(01:06:32):
that you're trying to screen for you have to make
a new test. It's an extra cost. The development of
that test is very very difficult, and essentially you have
to make the case that it's good for public health
to be screening for something that's one in a million, right.

Speaker 2 (01:06:46):
Right, So it's using the same logic really as standard
newborn screening, but you're leveraging this genomic sequencing technology, so
you're able to cast an even wider net than standard
newborn approaches.

Speaker 3 (01:06:58):
Screening approaches, a much wider net from like a parent's perspective,
especially maybe someone who doesn't really have a medical background.
How would this process of maybe being involved in the
Guardian study or doing like a genomic screening on your newborn,
how would that be different from a parent's perspective than
just standard screening.

Speaker 4 (01:07:18):
So again, a lot of the same follow up sort
of happens. You get called back. You might have something
we need to bring you back to see. We have
a different type of a test to check to see
if indeed this is a problem. Now, sometimes that different
type of test might be a genetic test, right, because

(01:07:40):
it's a different type of a test that says that, yes,
this biochemical problem was there. Usually though it's a different
you know, So for an immune deficiency, you know, we
would look for cells in the immune system to see
if they're missing.

Speaker 1 (01:07:52):
Or they're not missing or something like that.

Speaker 4 (01:07:54):
Right, so you you'd have to come in for another
test and during that time, you know, that is fraught
because we're not saying definitively that we know that there's
an issue, but this is the way that we're going
to find out is with this extra task and that
test might take DAR two or three you know, to
come back, and that of course is you know, can

(01:08:14):
be trying. Although you know that's not terribly different than
what has already done with the regular newborn screen.

Speaker 2 (01:08:22):
And I'm wondering if there are any stories that you
can share of children whose genetic condition was detected using
this genomic screening in Guardian after being missed by traditional methods.

Speaker 4 (01:08:34):
There actually are several stories with a similar theme, which
is again my specialty is in genetic diseases of the
immune system, and so we have a huge number, huge
number of these that we've already put into Guardian, and
many more which we are hoping to incorporate into Guardian,

(01:08:57):
just because we know that many of these are actionable
right in some way or the other.

Speaker 5 (01:09:02):
There's one of the cases that we saw was of
a boy who had a genetic mutation that was associated
with severe combined immune deficiency.

Speaker 4 (01:09:14):
The boy in the bubble, okay, and the boy in
the bubble couldn't get that bow Mara transplant to work
because he was already sick and older. But we do
know ninety plus percent of babies who are transplanted before
they get sick, usually before three months of age, and

(01:09:35):
will have lifetime survival cure, right, which is incredible. Otherwise
there are life threading infections which can happen. Once those
infections happen, the survival drops substantially. We are able to
keep people alive much more than the boy in the
bubble was found without having to keep them in a bubble,

(01:09:57):
but it's still they must get a transplant to be
to be cured. In this particular case, the variant that
we found had been seen in two other people, both
of whom did not have early on set infections. It
happened later and and so not surprisingly, we do have
a screen in that chemical screen, there's there's a screen

(01:10:20):
for severe one version of severe combined immune deficiency that
did not pick up did not pick up this problem
in this in this boy, and so you know, there
the parents were We're told this is the story and
the mom said, let's fix this as soon as we
possibly can. The sibling was a matched donor, went to

(01:10:44):
school the day after whatever after being a phone marrow donor.
And what did you do? Uh last week? Oh, I
saved my brother's wife and and and that was what
you know, the young sibling said about this this child, Uh, yeah,
he's doing great.

Speaker 3 (01:11:01):
What a doing right now?

Speaker 2 (01:11:03):
He'll never know that.

Speaker 4 (01:11:04):
He was sick. But the parents, you know, are quite
thrilled that this was found.

Speaker 2 (01:11:10):
Yeah.

Speaker 3 (01:11:11):
How does it feel for you, you know, as a researcher,
as a clinician, to be involved in this kind of work.

Speaker 4 (01:11:19):
I'm trying to think of the best way to put it.
I can't get enough of it. We need to be
moving at light speed here because there literally are kids
who are being born where there is something to actually capture,
right and to do something about, not even as you know, Oh,
maybe this may be that there are people with concrete things.

(01:11:40):
There are people who are in the hospital now where
if we had screened them, they wouldn't be in the
hospital now, right. I just feel an urgency, I guess,
is the best way to put it. To try to
get this implemented as widely as possible, and to be
doing all that work to fill up the things that

(01:12:03):
can be treated and have those treatments ready right, to
fill up the list, you know, to to say these
are things that we can do. And then also where
it is more ethically difficult, that we start confronting those
questions in advance so that we are we are able
to move forward with a regular standard of care for

(01:12:24):
for these types of things. There's a whole separate question
about if you know about a syndrome that can't be
treated right right, right right, That's a.

Speaker 2 (01:12:33):
Separate, separate question, a separate question.

Speaker 4 (01:12:36):
Yeah, but a question that might make it a little
bit tricky as well. Are there somewhere we do want
to know so that someone's working on it to find
that right And and there may be ways of doing
that type of a thing where you anonymize the medical
records and the and the sequences. And that allows researchers

(01:12:58):
like me to go into databases like that and say, okay, listen,
I'm studying this particular gene or this particular variant. What
what has this resulted in your in your database? And
then now I could start working on you know, understand
why that gene causes a problem, right, and and actually

(01:13:20):
then start working on a cure. So we need to
have systems ready to do things like that.

Speaker 2 (01:13:26):
Yeah, it's I mean, and it sounds like there are
so many different avenues for the wider application of the
type of screening that Guardian is doing, and then these
you know, ethical considerations as you discussed, and then just
research opportunities. I mean, there is It seems like we're
really on or maybe even over the threshold of where

(01:13:47):
genome sequencing will provide so many answers and also invite
more questions. And this was just such a fascinating conversation
and we really just can't thank you enough for taking
the time to chat with us today.

Speaker 3 (01:14:01):
Yeah, thank you so much.

Speaker 4 (01:14:03):
It was a pleasure.

Speaker 2 (01:14:22):
Thank you again so much to doctor Milner for taking
the time to chat with us about the future of
newborn screening and the Guardian project. I just I love it. Yeah,
so again, if you would like to know more about
whole genome sequencing and Guardian, there's a great episode of
Advances and Care and also all of the episodes are amazing,
but this episode is called Newborn gene Sequencing, expanding early

(01:14:44):
detection of treatable diseases again. It was released in March.
It has some great information about about what this work
has accomplished so far, which is a lot.

Speaker 3 (01:14:53):
I love it.

Speaker 2 (01:14:54):
I love it. Yeah.

Speaker 3 (01:14:57):
Well, if you also just want to know more by reading,
we have a list of sources for Youah.

Speaker 2 (01:15:02):
We do, we do. I have a bunch of different papers.
I'm gonna shout out three here. One is by Holtzmid
and Watson from nineteen ninety seven called Effective Genetic Testing
in the United States, Final Report of the Task Force
on Genetic Testing, and this was where I got a
lot of the history of newborn screening. And by slusec

(01:15:23):
at All from twenty twenty two, Psychosocial Issues related to
Newborn Screening, A Systematic Review and Synthesis, and then finally
by mccandalis and Wright twenty nineteen, Mandatory Newborn Screening in
the US, History, Current Status, and Existential Challenges.

Speaker 3 (01:15:40):
Aaron I also read that Psychosocial Issues one. I really
liked that paper. Yeah yeah, I didn't talk about it
because I felt like you did such a good job.
But that's on my list too. I also have a
bunch of papers just about, like you know, newborn screen
I mean. One was called an overview of newborn screening.
It doesn't get more straightforward than that. That was from
twenty ten by Levy. There was also newborn screening from

(01:16:03):
Clinics and parent Aetology twenty fifteen. I have a few though,
like newer ones about the whole genome sequencing aspect of it.
And then I also have a link to if you
want to know you like, in your state, what are
they testing for? You can go to babies First test
dot org and they have a list of state by state.
You can look up your state, figure out what they're
testing for and all of that kind of stuff, which

(01:16:24):
is great, and there is lots more there on our
website This podcast will Kill You dot com under the
episodes tab check it out.

Speaker 2 (01:16:33):
A big thank you again to the guests that were
featured in this episode. Jessica your first hand account, thank you,
thank you, and doctor Milner again, thanks for taking the
time and providing such important context for this really amazing technology.

Speaker 3 (01:16:47):
Yeah, thank you, thank you so much. Thank you also
to Bloodmobile for providing the music for this episode and
every single one of our episodes.

Speaker 2 (01:16:56):
Seriously, seriously, seriously, thanks Dan. Thank you also to Tom
and Leanna and Brent and Pete and Jess and Mike
and everyone who is involved at exactly right and helping
make this podcast happen.

Speaker 3 (01:17:10):
Thank you. We couldn't do it without you quite literally
literally thank you. I mean to you at all. If
you're listening still, I can't believe that you listened all
the way to the end. That's wild. I thank you
for doing that. And if you're watching, thank you for
doing more.

Speaker 2 (01:17:28):
Van A White hands tell this is why I don't
have a job as Vana White.

Speaker 3 (01:17:33):
But thank you so much for listening and watching, and
especially to our patrons for your support. It really doesn't
mean to watch us, even though I am being ridiculous
right now. I love it.

Speaker 2 (01:17:41):
I love it well.

Speaker 6 (01:17:43):
Until next time, wash your hands, you filthy animals.

Speaker 2 (01:18:02):
Um um