Okay, walk with me on this one. It's
going to be kind of a journey. So, me
and my family recently welcomed our
second kid into the mix. I know, right?
And that means in addition to the
souling joy and backbreaking sleep
deprivation that comes with bringing a
new life into the world, we had the
super fun experience of spending 48
hours obsessing over something called
Billy Rubin.
>> Oh, and do y'all know what Billy Rubin
is or why it's such a big deal in the
first couple of days of your life? You
don't? Awesome. Get this. Turns out in
those moments right after you're first
brought into the world, you've got a lot
going on. You're suddenly hit with a
whole mountain of responsibilities at
the chemical level. And chief among
them, you're suddenly in charge of
modifying your entire blood supply so
that you're better able to breathe out
in the world. Specifically, it's now
your job to break down this character.
He the ancient allimportant iron carrier
responsible for fing oxygen through your
circulatory system. He can be incredibly
dangerous if it breaks down in the wrong
way. So, your body is constantly
cracking this little ring apart and
recycling it once your red blood cells
get worn out. But for reasons I'll get
into, that's a ton of responsibility for
a newborn liver to suddenly be saddled
with. So, up to 60% of all infants fall
behind and develop a buildup of the end
product of hem catabolism, Billy Rubin.
And that leads to a very common
condition called neonatal jaundice. For
the vast majority of cases, this
resolves quickly as you gradually catch
up to all your newborn responsibilities.
So, it primarily serves as the very
first existential crisis new parents
experience as they try to get a handle
on exactly what it means to bring a life
into the world. And here's what blew my
mind as I kind of overressearched this
before we even had kids. It turns out
that for a small number of cases,
neonatal jaundice might be tied to
issues with the microbiome. You know,
the trillions of helpful bacteria that
live in your gut. Incredibly, your body
doesn't break down Billy Rubin all the
way. You process it most of the way and
then dump it on your gut where bacterial
enzymes actually finish the job, which
is so wild to me. Why is this system so
complicated and so prone to get out of
whack from the drop? Answering this
question sent me on an absolute journey
while I anxiously waited on the arrival
of the latest member of Team Clockwork.
There's a lot of incredible biology
surrounding Billy Rubin in the first few
hours of your life and beyond. Enough
that I just honestly had to share it
with you. Despite how deliriously sleepd
deprived I am, let's go ahead and
explore all the incredible chemistry
surrounding one of your most critically
important metabolic processes.
And hey, welcome back to Clockwork, a
show about the chemistry powering your
foundations. Subscribe if you want a
better understanding of how your
chemistry roots you to the world. And
check out our community on Patreon to
see our latest sticker packs, temporary
tattoos, and papercraft molecules. But
anyway, let's get right into exploring
everything about Billy Rubin. Billy
Rubin is the second step in breaking
down hem groups, specifically the heem B
found in your red blood cells. Other
heem variants can be found all over your
body with another god tier specimen heem
C being responsible for connecting
subunits of your electron transport
chain via cytochrome C in your
mitochondria. Looking at hem though, at
the center of this ring of carbon atoms
is four nitrogens that stably hold on to
a pretty reactive iron atom. Check out
my last video to see just how useful he
is for breathing and like being alive
and stuff. Your blood cells use the
reactivity of this iron atom to grab
onto and let go of oxygen, transporting
O2 exactly where it needs to go,
depending on the context, but you know
all about that from the very first video
I made. Check that out if you haven't.
But importantly, the reactivity of this
hem group can get out of hand if it
breaks in the wrong way, leading to the
creation of reactive oxygen species and
all sorts of other cellular mayhem. So
rather than recycling old hem groups and
like leaving it up to chance, evolution
has opted for the safer and more
expensive option, completely destroying
old heem molecules and rebuilding them
from scratch in your mitochondria.
Therefore, your body is constantly
destroying older red blood cells before
they can get too worn out, usually after
about 3 to 4 months, scrapping them for
parts. Specialized macrofasages in your
spleen and liver take care of this,
detecting worn out red blood cells and
devouring them. And this is where he
breakdown kicks off. Your macroofages
crack open this ring, freeing the iron
inside, creating a green intermediate
called Billy Verden. And then
immediately they're going to break it
down a little bit more into the main
character of this episode, Billy Rubin.
Now, the important thing here is that
Billy Rubin is not water soluble. So, we
can't just like dump it off into the
bloodstream and hope for the best.
Instead, Billy Rubin is going to get
packaged inside this specialized blood
protein, which is human serum albumin.
And from there, it's going to get
transported to the liver. And your liver
only has one job here, and that's
sticking two sugar derivatives onto
Billy Rubin, conjugating it, which makes
it water- soluble and therefore way
easier to transport. Now, this is the
part of the process where a lot of
newborns find themselves in trouble. And
there's two main factors driving the
problem. First up, newborns are cracking
these hem rings way faster than adults,
producing basically double the amount of
Billy Rubin that an adult would. And
that's because in order to adapt to
breathing air, you basically spend the
first couple of months of your life
replacing your entire blood supply. And
sidebar, let me unpack that real quick.
In order to adequately absorb oxygen
from your mom, you produce a specialized
version of hemoglobin while you're, you
know, a fetus. This is a fetal
hemoglobin, and it's just slightly
better at binding to oxygen than adult
hemoglobin, meaning that fetal red blood
cells can easily pull oxygen from their
mom's hemoglobin in the placenta. Adult
hemoglobin is a balanced mix of two
alpha and two beta subunits, while fetal
hemoglobin swaps those betas for two
gamma subunits, which are just a little
bit better at binding a little tighter
to oxygen. But the thing is,
hemoglobin's job isn't holding oxygen,
though. It's transporting oxygen.
Meaning that to be successful at its
job, it has to be equally good at
letting oxygen go. So, right around the
moment you're born, you produce a
transcription factor that silences the
fetal hemoglobin gene forever. And you
spend roughly the first 6 months of your
life destroying your entire fetal blood
supply and replacing it with adult
hemoglobin better suited for breathing
air out in the open world which adds up
to newborns producing effectively double
the volume of Billy Rubin that an adult
would. Now this Billy Rubin overload
would be hard enough to deal with but
there's a second major factor here. Your
liver simply is not building enough of a
Billy Rubin cleanup squad fast enough.
Now in your liver cells you've got this
enzyme UDP glucuranial transferase. you
know, UDP GT and its job is to stick
those two sugars onto Billy Rubin. Now,
as an adult, your liver is positively
stocked with these fellas. But on day
one, you are seriously underprepared. At
birth, most infants have only built
about 1% of the UDP GT they need. And
after a month, you're lucky if you've
assembled maybe 10% of the Billy Rubin
cleanup squad you need, and you only
achieve 100% somewhere around your 3 to
4 month mark. It's cool that the growth
rate is kind of exponential in this way,
but that initial lag is a huge issue.
And also hilariously, it turns out that
your little baby liver tries to cut
corners to keep up with demand. Instead
of the full job sticking two of these
sugars onto a Billy Rubin molecule,
we're going to try to get by with just
one. Sure, a half conjugated Billy Rubin
still dissolves in water just fine, but
stability is the issue here. Half
conjugated Billy Rubin isn't going to
hold this structure nearly as well as
fully conjugated Billy Rubin, meaning
this little sugar, you know, glucuronic
acid, is prone to pop off anytime,
anywhere. And that means that
deconjugated Billy Rubin is going to be
falling out of solution all over the
place on its way to being removed by
your intestines in those first few
months of your life. Since Billy Rubin
dissolves in fats and oils, it's most
likely to build up in your skin and
eyeballs and that's going to turn those
tissues a shade of yellow. This by
itself isn't dangerous, but if you don't
get that Billy Rubin buildup under
control, there can be rare dangerous
complications like toxic levels of Billy
Rubin building up in other fatty parts
of the body like the brain causing a
very dangerous kind of swelling. But
let's stick to the basic scenario first.
And to review, here's the general
landscape of our problem here. In our
first hours of life, we're cranking out
Billy Rubin at double the normal
production rate, while our dumb baby
liver has only produced 1% of our Billy
Rubin cleanup crew, which is an
incredible mismatch of supply and
capacity. So, it's no wonder that most
newborns get hit with some form of
neonatal jaundice. But this mismatch
stuck with me. That is an incredibly
wide gap. Evolution can be way more
clever than this. Is there any important
reason our livers are completely fine
with ramping up this slowly when the
stakes are this high on day one? And
again, answering this question in
particular sent me on a wild journey.
And I only really have a clear-ish
answer thanks to a paper that was only
published last year. As it turns out,
one angle we can use to explore this
problem is the simple fact that we
co-evolved with our microbiome. So now
sure you check them out. But anyway, let's get back to Billy Rubin. As it
turns out, we got a lot of help getting
rid of this yellow gunk once it hits our
gut. And this is the paper that cracked
things wide open for me. This awesome
team from the University of Maryland and
the National Institutes of Health
finally isolated the enzyme from our
microbiome that helps finish processing
Billy Rubin in our gut. In so doing,
they also proposed a bunch of new
connections to help make sense of this
Billy Rubin problem. There are so many
ways to tackle the back half of Billy
Rubin processing. But let's just drill
down into the basic pathway first. First
up, let's just rock through the core
pathway that gets Billy Rubin from our
liver to our exit points. From the
perspective of our body, the story
should end with conjugated Billy Rubin.
This fella should stay dissolved in
water and then go out the back door with
the rest of the really toxic waste. And
yet, lots of that conjugated Billy Rubin
breaks back down into raw Billy Rubin
once it hits our intestine. And that's
even when you're an adult. More on that
in a second. Again, raw Billy Rubin
could pose a big problem. But luckily,
there are friendly critters in our
microbiome who process this into
eurobillanogen, making it a little bit
more water- soluble and therefore way
safer to dispose of. Urbilanogen is then
either further broken down into
stircoilanogen in our gut by different
bacteria or it slips back into our
bloodstream where the kidneys can have
an easier time filtering it out which
for the most part eliminates any of the
danger posed by excess Billy Rubin. All
right, cool. So, thanks to our bacteria
bros, we've got two clean undramatic
exits for Billy Rubin. Nice. But why is
conjugated Billy Rubin breaking down in
the first place? Now for newborns, we
already explored the reason why these
UDPGT enzymes in the liver are so
overwhelmed by the Billy Rubin load that
they're only half conjugating most of
the waste. Meaning that a lot of this
Billy Rubin is bound to accidentally
break down before it reaches the exit.
But that's only part of the problem,
which is why we now need to talk about
the microbiome. And this is in no way
comprehensive because the microbiome is
such a massive topic and such an active
area of study. But basically, the human
gut is colonized by trillions of helpful
bacterial species that partner with us
in exchange for a safe place to live,
amongst other things. You aren't just a
person. You're an ecosystem, a
rainforest's worth of species diversity,
complex to a degree that is difficult to
fathom. Your bacterial partners confer a
lot of really important benefits to you,
but I don't want to get bogged down in
the basics. Let's go back to this paper
and zero in on Billy Rubin specifically.
And now, get this. It's likely that some
species of your microbiome are
deconjongjugating Billy Rubin in your
gut, thereby in some ways causing this
problem in the first place. Not when
you're an infant, but once your liver
has its act together and you're capable
of properly packaging this goo. But
there's a balance here once you're old
enough because there's just as many
species in your microbiome that grab
onto Billy Rubin before it can leave
your gut and get all jaundicey. The
researchers behind this paper managed to
isolate the genes coding for this little
protein complex in five different
species found around the microbiome. The
workhorse here is Billy Rubin reductase
which complexes with this little
electron cannon and blasts Billy Rubin
with electrons enough to reduce it to
eurobillinogen. Again, this conversion
to eurobilinogen disarms the danger
Billy Rubin poses to our body. It's way
less reactive and far easier to dissolve
in water, which I mean that's cool, I
guess. But that leaves us with a really
big question. Why? If Billy Rubin can be
toxic to us, what on earth would these
little bacteria want it for? And the
answer here ties into that weird
mismatch we see in neonatal jaundice.
Because here's the plot twist. Yes,
Billy Rubin can be very, very toxic in
heavy concentrations. But in small
amounts, Billy Rubin actually functions
as one of the most powerful antioxidants
produced by the human body. And this
completely blew my mind when I first
learned about it because it is very
counterintuitive. To keep it brief, an
antioxidant is any compound that can
help disarm free radicals in your cells.
Your metabolism is actually a pretty
violent process. And just using oxygen
to breathe means that we're accidentally
producing these rogue compounds all the
time. You've probably heard of
antioxidant supplements that supposedly
help you clean these things up. But your
body naturally produces different
specific antioxidants for specific free
radical situations. And antioxidants
alone are a super complex topic. So
don't jump to conclusions based on
anything in this video. But yeah,
depending on the situation, your body
might use hem degradation as a quick
antioxidant source in response to
oxidative stress in your cells. And hey,
maybe you can see where this is going.
Can you guess one of the moments in your
life where you're kind of guaranteed to
have the most oxidative stress? That's
right. It's those first few hours and
days right after you're born. And this
next part is extremely not medical
advice. I could not be further from a
doctor. But it could be that our livers
are totally fine with being slow to
start this Billy Rubin cleanup process
because this excess of Billy Rubin
potentially maybe confers a little
protection during the incredibly
stressful transition to being out in the
world and actually breathing air and
stuff. And meanwhile, we do have our
microbiome to help while our livers get
their act together because the structure
of Billy Rubin also allows it to act as
a terminal electron acceptor in certain
anorobic metabolisms. Turns out a
significant segment of our microbiome is
composed of anorobic critters who use
all the little nooks and crannies in our
gut as a place to hide from the
pernitious influence of oxygen. And some
of those fellas may in fact use Billy
Rubin and urbanogen to breathe which is
wild. Now make sure you check out the
last video I made to learn about how
certain bacteria breathe using rocks
instead of oxygen if you want more
detail on this point. But I don't want
to like be here too long. Again, there
is so much more research to do here. But
after this paper identified the genes
that code for Billy Rubin reductase,
they cross-referenced those genes with
known databases of metagenomes,
basically a library of all the genetic
information in the microbiomes of
specific individuals, and found that a
lot of sampled folks are missing
bacteria that code for Billy Rubin
reductase in the first 3-ish months of
their life, which is precisely when
you're the most likely to get hit with
neonatal jaundice. Now, of course, these
samples are very limited. So, the
picture here can get a lot more
complicated pretty quickly, but it is so
cool to see this weird little economy at
play. It might be that our body simply
leans in to an excess of Billy Rubin to
help deal with the stress of existing
all of a sudden while simultaneously
trusting our bacterial partners to
protect us from things getting out of
hand. Which is why so many cases of
neonatal jaundice end up not being a big
deal at all. But more importantly, it is
impossible to know in the moment if a
case of jaundice is going to be
problematic or not. Which is why it's
really important to listen to your
pediatrician if you're currently going
through this as a parent. Things like
phototherapy are really good at breaking
Billy Rubin down into something your
body can handle a little bit better with
ease. This video only exists to add
context around this messy topic. A few
hypothetical wise to hopefully ease your
mind while you're potentially soldiering
through this situation. So, deep breath.
Let's complete the picture. Here's a
simplified summary of what might be
going on here for some folks in regards
to Billy Rubin processing. In the first
6ish months of your life, you're
upgrading your blood supply to make it
airrated as quickly as possible, which
is dumping a ton of Billy Rubin onto a
little baby liver that is simply not
ready for this much responsibility this
quickly, which means that your gut and
other tissues are going to be full of
deconjugated Billy Rubin as it falls out
of solution. Incredibly, it might be
that your body is fine with this because
of Billy Rubin's blanket antioxidant
properties. Luckily, at the same time,
as your microbiome develops alongside
you, some species of your gut flora will
use that billy rubin to breathe,
processing it into eurobilinogen, which
is a great solution to that problem. And
sure, this means that throughout your
life, those bacteria will also keep
deconjugating Billy Rubin after your
liver has gotten its act together, but
as long as they keep making urbanogen at
the end, it all works out pretty okay.
Because that's the genuinely fascinating
thing about being here on this earth. It
is amazing how much of an economy we've
built up with our microbial partners.
The microbiome's goofy, half-hazard
processing of Billy Rubin makes our own
metabolism safer in the long run because
their circumstances allow them to
benefit tremendously from Billy Rubin's
reactivity. But I love how papers like
these help us understand the economy of
being a multisellular species with all
sorts of commensal partnerships. It is
amazing to see all the compromises and
all the goofy little trade-offs our
cells have to make just to keep us alive
at baseline. a little longer. We're at
this incredible moment where our view
into our inner molecular complexity is
becoming so rich and interconnected. And
that means we're starting to really
unravel some of the deeper connections
we have to this ecosystem we're hosting
in our gut. Don't take anything in this
video as gospel, though, as there's just
so much more to discover about the
microbiome, and these connections are
complicated and easily prone to
revision. But finding the wonder in
these connections has made being a
parent all the more magical. It is
astounding how much effort we put into
those first few weeks of our time here
on this good earth. And while I'm
honestly glad it's impossible for me to
remember my first years of life, bearing
witness to that effort firsthand has
been a loud reminder of one of the core
philosophies behind this channel. Life
just works. Even though your cells have
to make all those compromises and even
though your metabolism can cause all
sorts of mayhem, life really genuinely
wants you to be here. And every one of
your trillions of cells will work so
hard just to push you a little forward
second by second. It's hard to remember
that sometimes, especially since I
really haven't slept more than like
three hours in the last 6 months. But in
the end, I am just so glad I get
firstirhand evidence of just how much
effort we put in to just be. Either way,
that's a good enough place to end this.
I really appreciate your time. Thank you
so much for being here.
And hey, thanks so much for making it to
the end of this video. If you enjoyed
this video, please make sure you like
and subscribe so we can get a stronger
foothold on this platform. At the same
time, it would mean everything to me and
my family if you look at everything we
have on offer at
patreon.com/clockworkshow.
Projects this detailheavy live and die
by community support. and I'm working
hard to make sure folks in my audience
get a lot of benefits from their
contributions to our community. At the
same time, feel free to check out
watchclockwork.com and sign up for our
email list and check out the hem hat I
made in conjunction with this video if
that's more your speed. Either way, if
you made it this far, I would love to
know what your favorite muscle is. It's
important for the next video we're going
to be publishing soon. To be honest, the
biggest help you can provide this
channel is making it this far. You've
already done it, and I cannot begin to
express how much I appreciate you being
here right now. things will get back on
track a little more now that I'm
actually pushing more than like 4 hours
of sleep for the first time in months.
But I mean, let's hedge our bets a
little bit. Either way, that's all for
now, though. I really appreciate your
time, and as always, I'd like to leave
you with peace, love, and fully
conjugated Billy Rubin. Everyone, be
well. Thank you so much.