Episode 170: Charles Serhan on the use of specialized pro-resolving mediators to resolve inflammation

Episode Transcript
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(00:00):
Welcome to Stem talk. Stem talk. Stem bangkok.
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Welcome to Stem talk. Where we introduce you
to fascinating people who passionately inhabit the scientific
and technical frontiers of our society.
Hello? I am David Lame and I'm stepping
in today to help host today's episode of

(00:21):
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behind the curtain, Doctor Ken Ford. I c's
director and Chairman of the double secret selection
committee that selects all of the guests who
appear on the stem talk show. Hello, David.
Great to be here. For regular listeners of
Stem talk, you may recall that David was
our guest guns Stem talk episode 69.
David is a physical medicine and

(00:42):
rehabilitation physician who allows a pensacola practice just
a few blocks from I.
Where we're sitting now. His practice focuses on
lifestyle and performance medicine. He is also a
visiting research scientist here at I.
Thank you, Ken for inviting me today to
c host the interview with Doctor Charles Sir,
and a good friend of mine who has
a harvard professor best known for his discovery

(01:04):
of specialized per resolution mediator,
Sp are molecules that can activate natural resolution
of inflammation and help to avoid anti inflammatory
drugs. The discovery of Sp has been described
as spur a paradigm shift in understanding of
inflammation and human disease. Charles has the Simon
Gel professor of Anesthesia at Harvard Medical School,

(01:25):
and the director of the center of experimental
therapeutics and fusion injury at B him and
Women's hospital. He is also a c director
of the B
Research Institute.
Before we get to our interview with Charles,
we have some housekeeping to take care of.
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An now on today's interview with doctor Charles
sure.
Stem talk stem bangkok laptop. Stem, pot stem

(03:32):
talk.
Charles, I understand you were born in Brooklyn,
and that your father was a French Lebanese,
and your mother was italian and both were
born in New York City as a youth
You were quite passionate about music. You learned
to play the vibrant phone in junior high
school and became so accomplished that you played
professionally for about a year before going to
college.

(03:52):
How did you end up as a scientist
rather than a musician?
Well,
I felt that I still feel today that
I could
help many more people
via
science
than I ever could in
playing music.
Although,
I have to say that I still love
playing and I feel

(04:15):
very comfortable
behind the vibes and
It's like second major to me.
What kind of vi phone did you play?
I have a must
if that's what you mean. Yeah.
Yeah. An m 55.
Mh.
And
those are
known as the 1 night because you could

(04:37):
travel around with them. But someday,
I will get
the gold set of fives, which is the
studio
set.
Still looking forward to that.
There used to be guy up in the
Boston area. I don't know if he's still
up there, Gary Burton.
Oh, draw 1 of my heroes. Yeah. He

(04:58):
was... I was in the music business in
the early seventies, and we used to book
him, and he he was a very talented
person.
4 mall pro. Yes. I I like to
replace some carry burton tunes.
He was dean of Berkeley, as you know
for some time. And a fantastic

(05:18):
musician, and he comes from
the genre of big band.
And
but his quart at work and
the recordings he did with Chi korea
just
phenomenal. Right. No there was a period when
he he was really amazing you was... He
was experienced and skilled and still youthful at

(05:40):
1 point, you know, and it it was
wonderful time with Chick korea and others,
he's he's etched into my memory.
Oh, yeah. I
would always
turn to play with my group when I
was in school. 1 of his tunes called
c journey.
Yes. And

(06:00):
fantastic.
You know, you mentioned that you had always
liked science and had done well in science
in school, which doesn't surprise me What was
it about science that you particularly enjoyed? You
said that you felt you could do more
good in science for more people than in
music, but but, you know, was there a
particular thing about studying science that you really

(06:22):
mostly enjoyed?
I
really
enjoy
the rigor and objectivity
and
the ability to
test hypothesis
do
experiments,
doing experiments is,
yeah, nothing more fun than that.

(06:45):
After you were a professional musician, you you
went to the state University of New York
at Stone Brook. Yeah. I was lucky. Yeah.
Eddie and you studied biochemistry and amino history
there?
Biochemistry
was my major
and
chemistry.
The his chemistry side came

(07:05):
in my research project. I was really fortunate
to work with very good I
in the Department of pathology.
Yeah. So... And for people in terms of
the audience and understanding, this is
something that's used to diagnose cancer and predict
treatment responses

(07:26):
and
likely prognosis of the disease.
In terms of your your switch from, you
know, musician to biomedical science, was there anything
that carried over in terms of the music
side that you felt carried into the scientific
side.
Yes. That's an interesting point.
Yeah. Many things that I learned in music

(07:46):
translate
to science. For example,
if you really wanted to play well, you
had to study and practice your scales and
you did this routinely
all musicians do.
And
it's like learning a language
and in science,
the same is true.

(08:07):
You need to learn the language
and
study and practice
every day.
Makes sense? Does for sure. So after earning
your bachelor's degree, 1 of your professors
convinced you to head off to York University
for your master's and Phd
and also you worked in the lab of

(08:28):
Gerald Wi at Woods home marine biological laboratory.
This all seems like a must been a
major move.
In your development. Can you talk about that
experience and how it all came about?
Well,
Ken, this
was
would set me on my path, and I
was very, very fortunate. So I'll

(08:49):
describe this in a
nutshell. I was very enthusiastic
as an undergraduate. I took graduate school courses.
As an undergraduate.
And 1 of the courses was in
the bio physics
of
membranes,
and we used
as a comp in in reading text

(09:13):
Gerald Weiss
book that he put together
called cell membranes,
which was a, a group of articles that
were at the scientific
American level that were published in
hospital practice.
The other graduate school course that I took
as an undergraduate was in cell cycle

(09:35):
kinetics,
and
I really enjoyed
mathematical modeling.
And that professor, professor Edge
encouraged me to
to para and do something serious.
So I was very fortunate to go to
Nyu.
And get a Nih

(09:57):
pre doctor fellowship
at the time,
and I was in the first year,
medical school class,
and Gerald Wei
came to give a lecture
on the cell biology
of le.
And he had just returned from Paris.

(10:17):
I remember this clearly.
He had this movie of Lucas
chemo taxing, and I just thought that was
so cool.
So I
went up to speak to him after class.
He said, oh, come up to my office,
and
his office was in Bellevue Hospital

(10:39):
and where his lab was
department of Medicine. So I went up to
see him and he said, Oh, what are
you doing this summer? So I said I
haven't made any plans yet. He goes could,
because you're coming to
woods,
the marine biological laboratories
at Woods.
Wow. This was incredible.

(11:00):
What an opportunity. We worked on
white luke... White blood cells, lu sites from
dog fish.
But the entire
environment was really stimulating,
and
I had an opportunity to
work that summer
with
Bank Samuel
daughter,

(11:21):
who was
working with us in the lab.
And then
Samuel came at the end of the summer,
we were
really lucky.
We won the
mb award that year, and I presented on
behalf of the lab
that was fun. So He I asked me
to tell him about what we were doing.

(11:42):
And I did
and he looked at me and said,
charles,
when you finish
there'll be a place for you in Stockholm.
I said, wow.
So I hadn't really thought about doing something
like that, but it changed all my plans,

(12:03):
and I
decided yes. I'm going to stockholm on.
I'll finish early.
And I was really fortunate to continue a
collaboration
between the Wei lab and with Samuel
and 2
of my
publications with Samuel that were part of my

(12:24):
thesis
were
cited
and
bank Samuel
Nobel
lecture.
I was very proud of that, and I'm
still proud of that today. Yeah, that's amazing.
And this kinda led you into the
focus on ne
membrane remodeling for your Phd. Is that right?

(12:45):
Yes.
I was really fascinated
with the process of ph
and how these cells defend us by seeking
out
bacteria and foreign invaders
and then
quickly
in matter of seconds and minutes,
fa
these
organisms

(13:05):
and then destroy them To do that,
neutrophils have to very very rapidly
remodel their membranes make new phospholipids
to expand
the surface area to be able to
and inform a fa l vacuum that they
then pour
the armament

(13:26):
in them that break down
the
bacteria and kill them and
This is
very well known area of
medicine and biology,
and
that process was discovered by
Mitch K,
and

(13:48):
the late 18 hundreds, and and he received
a Nobel prize
in physiology medicine
for that
discovery and the innate immune
response.
Yeah. It's an it's incredible. And I I
understand that after you earned your Phd,
that at you you had mentioned the Caroline
Institute. Is that where you met your your

(14:09):
future wife?
Yes.
Samuel used to joke that
said, oh, yeah. Trolley was
very productive. He even
met his wife.
I think care let's yes. We met on
the cafeteria
line
during lunch 1 day,

(14:30):
and my wife there was
studying medicine
and finishing up her medical degree at the
time.
It seems clear that you are quite fortunate
and have been quite fortunate. To have a
number of strong and ineffective mentors where you
in school, 1 who stands out is Michael
He bird a 2 time winner of the

(14:52):
last girl award in medicine.
He stands out particularly because of the advice
he gave you, I think and how to
be a good scientist? What was his advice
and what impacted did it have?
Well,
doctor He burke was really
special. And
he was an organic chemist by training,

(15:12):
and someone in the Dean's office noticed that
I had a background
in chemistry and that like chemistry. And
I remember very clearly this woman value cocoon.
She said, oh, you should go up and
Talk with Doctor He burke, He needs someone
to help him at this time. And I
did and

(15:32):
worked with doctor to Har park just he
and I
in this very small
land.
His career was at Columbia University,
and he was the scientific
grandfather
of Bar Ben
who
also received a Nobel prize

(15:53):
for his work on antigen antibody combining sites.
So when they asked Doctor H,
about what
it took to become a good scientist, and
he
would always
chat with me, and he said 2 things.
Charles, you have to work on something that
you're passionate
about

(16:14):
because this will carry you through the difficult
times.
And second,
write everything down write all your
observations down
in your notebook and carry a second notebook,
that you can jot down your
observations and notes because in those notes
will be your discoveries

(16:36):
and I tried to
bring that message to all those that come
to work with me and my research program
costs.
I found them to be
absolutely essential. And I should point out that
Doctor Hard at that time,
was 91
years old, and he lived to a hundred

(16:58):
and 3, and I was the last person
to work with him. So I was fortunate
in so many ways.
He also encouraged me to go to work
with Gerald Weiss.
That's incredible. And speaking of, you know, in
terms of discoveries and amazing scientific

(17:18):
progression in the nineties,
you discover what became known as specialized pro
resolution mediator.
And most people don't realize, you know, that
there... There's even another pathway to the aspect
of,
inflammation that is active. And since that discovery,
you pioneered a new field of research in
the
utility of Sp

(17:39):
for all kinds of different diseases from chronic
pain, rheumatoid arthritis,
dental disease, macular
degeneration, cardiovascular disease, depression,
brain injury inflammation, conditions like arthritis. I mean,
it's basically a
necessary part of our body in terms of
healing and repair at that nobody really knew
existed before.

(18:00):
Just gonna jump in here and tell you
a little bit about that journey.
And the journey that was still on. You're
right in that when I was at the
Carolyn Institute,
we discovered the
these new molecules
and call them the lip
because they will like

(18:22):
interaction products,
and I
was
convinced
that
there were regulatory
mechanisms
that we didn't know about
to control
the production and actions of the le
and Samuel
part of his Nobel

(18:42):
citation is the discovery of the le.
And these are very potent
molecules
that
control
airway and smooth muscle
constriction and they're important in asthma
and in ana
shock
So my reasoning was very simple that there

(19:04):
must be some
other molecules
produce that could count regulate
these potent actions because why would the body
molecules
that could ultimately kill us.
Because didn't make sense in evolution. And
we already knew
that

(19:25):
platelets
when they become activated, they make t boxing,
that was another molecules that Samuel
discovered with Mats Hamburg at Car. They did
the structure el liquidation,
very elegant molecule,
only
15 to 30
second half life in vivo.

(19:46):
And this molecule
propagate,
platelet
aggregation and is essential for clock formation. So
there's another molecule
that counteract interacts
the actions of t
called pros.
Which was discovered by Sir John Veins group.

(20:06):
It's also an ara acid product is made
by the vascular and epithelium.
And
pros the cyclone
puts the brakes on
the platelet
aggregation response.
So this
already evidence
that
the physiology of counter

(20:28):
regulation
important in
the small molecule lipid mediator.
So when I came to Boston,
we didn't
yet know what the role of the
were.
We needed to do a lot more
investigations,
physiological experiments
and then

(20:49):
we had a Eureka
moment to the fellow
who came to work with me from Barcelona
Spain,
John Cla, and I work together and found
that
when we take Aspirin,
It was already known that Aspirin would block
the production of t boxing

(21:11):
and
pros.
And it's widely used as an inhibitor still
today, and that was part of the Nobel
citation for both Samuel
and ci on vein. They shared price in
19 82
in physiology of medicine.
What we found
is that Aspirin

(21:32):
triggered
lipid mediator,
not only blocked
frost the gland and in t
production
but it also triggered the bios
of what we called
aspirin triggered
lip
or,

(21:53):
lip that were
longer acting and a different
chi
this was really exciting,
and
I
then to devoted
our efforts to
making
my medics in stable analog of the aspirin
triggered my toxins because we thought this was

(22:15):
the stop signal.
For
excessive le site recruitment
and then worked for the next
10 years
with Be Bios,
sciences
and
shea Germany
to advance
an aspirin triggered lip
my.

(22:36):
Into clinical trials,
and it worked fine. There were 4
phase 1 dosing
trials and many, many preclinical models and animal
models demonstrating
that
the mime that we made
with
Bro shea was
very potent in reducing

(22:58):
Gi
inflammation
and it was queued up to end enter
trials for Ib
and eventually Crohn's disease.
And this was really exciting
but then
there took over the sharing and decided
that
Ib d was not on their

(23:19):
lists
of things to do,
and they
dropped the program, which was
so disappointing.
After having put in such a monumental effort,
but we learned a lot during those studies
And that's
the knowledge of the aspirin triggered like toxins

(23:43):
really opened the door to
uncovering the resolve,
which are also aspirin triggered lipid mediator,
and that's why when the families
of
resolve in pro resolving mediator that are made
during the resolution phase of inflammation.
Became clear as we did the structural el

(24:05):
liquidation. I went back and classified
all these molecules
as
specialized pro
mediator,
not because they're special, but but they have
a specialized
function
to put the brakes on ne
infiltration
and stimulate macrophages

(24:26):
to clear
ap, the cells, particularly ap
neutrophils, dose neutrophils that diet at the site
of battle
in
inflammation. And this is a very
important part of the pro
resolution
stimulation of clearance

(24:47):
of
inflammation.
So I know that's a bit of a
long answer, but I hope it gives you
a picture of how we
wandered into the resolution phase. A That was
a great answer. Thank you. According to scholar
Gps,
you've done more research in the field of
inflammation than any other scientist.

(25:09):
That's pretty remarkable. We will be talking a
lot about Sp today, but I'd like to
back up a little and set the stage
and ask you about the research and the
work you did that led to the discovery
previous to it. I suppose this journey of
yours really kind of started, when you're in
your post doc years at Karl
and studying
inflammation itself? What ent you about inflammation. I

(25:32):
mean, we all know it's... It has many,
many functions,
acute and chronic. But could you talk to
us a little bit about what really intrigued
you about inflammation and and point to you
in that direction?
Yeah. Can, when
I was a student
when I first learned about the innate immune

(25:52):
response.
And
inflammation,
I just felt that this was the keys
to all of medicine
and
surgery
and
that we needed to
understand
how the body
controls
the
acute inflammatory

(26:14):
response,
which is protective,
control it from preventing
collateral
tissue damage
and more
inflammation.
Yeah. So in in in simple terms, we
kinda think of inflammation as getting rid of
what's damaged, but also protecting what's healthy,

(26:34):
and there's different ways that we would discuss
inflammation
acute versus chronic, the the symptoms for the...
Kind for the audience. The symptoms of inflammation
would be pain redness and swelling typically. Like
you would get if you you know, got
a rug burn, cut your skin, rolled an
ankle something simple. But I've heard you say
that inflammation comes in many forms and that
we have what you referred to as new

(26:55):
villains of inflammation. And since we're talking a
little bit about inflammation, can you kinda give
us an overview of the different types of
inflammation? That we might talk about?
Sure.
I've come to learn that each of the
medical specialties
thinks about
inflammation differently.
It means different things

(27:16):
to
different specialties.
An op
thinks of
inflammation in the eye
very differently than
a surgeon and who is
themselves a inflammatory stimulus.
From the first cut.
Charles that's that's a great. I I just
love that. I I have a surgeon

(27:38):
the office 2 doors down for me here
at I c, and I love that description.
I think I'll describe him that way.
Well,
inflammation has been done since ancient times, the
times of celsius.
Ancient physicians
described as you put heat, redness,

(28:00):
pain, swelling and then
when Vi came along, it was the
the the loss of function.
So the different forms of
inflammation that are common to
most
clinicians and the general public is acute
inflammation, 1 that occurs rapidly

(28:21):
acute and then chronic
inflammation,
ongoing persistent
inflammation.
That 1 may see in
autoimmune diseases, for example. Or as we appreciate
today,
in neuro generative diseases.
Okay. So in the post genomic era,

(28:41):
my view is that
controlling
inflammation is the frontier of medicine and surgery
because most of the issues
that we face
in western societies
are the result of
excessive
inflammation. And

(29:01):
that's come to light. I would say only
in the past
10 years or so was more and more
cellular and molecular studies.
People arrived at this conclusion that, oh,
inflammation
is set
at hand here. Okay. So it in our
research,
it was important for us to define

(29:24):
very carefully
what is known as the acute inflammatory
response?
This is a programmed
repertoire of how
white blood cells,
specifically
neutrophils leave the post capillary v
and then arrive in tissues,
various tissues in the body to defend that

(29:47):
tissue.
When that process
is excessive
when there's an excessive
swarming
of neutrophils and
neutrophils swarm in,
and they move,
they need chemical signals
to
smell like sharks

(30:08):
moving to red blood cells, they swarm in.
When this warming
occurs to protect us from invaders or tissue
damage. If it's too much
collateral
damage occurs,
and that collateral damage,
propagate
inflammation. I think of good example

(30:30):
is in rheumatoid arthritis,
when
neutrophils swarm into the s,
if they spill
these enzymes that have you evolved to kill
bacteria
outside of the cell, if this
incomplete ph
if that membrane doesn't close

(30:51):
and seal
from the healthy tissue. The enzyme spill
reactive oxygen species spill and this
destroys the s
with time and leads to
spanish formation, which is
takes the smooth
surface and turns it into a s

(31:14):
surface,
and it leads to a lot of pain.
So
in the textbooks
of pathology
is very clear
that the acute inflammatory response
had a
resolution phase
when the area is cleared and the tissues

(31:35):
returned to
homeostasis.
That's what we focused on and asking what's
going on in this resolution phase.
It's self limited.
Okay.
Let's think about this for a second. Think
of having a small pimple on your skin
on the back of your hand.
The white of the pimple,

(31:57):
the p, if you will. Those are the
lucas sites that have
sworn to protect us
And
if you leave that, pimple alone for a
day or 2,
it completely
resolves.
So
what's going on there? The body has

(32:18):
resolution signals
to bring us back to homeostasis,
and that's what we set our guns
to
understand
and see if we could
learn
that process,
learn about those molecules?
Can we use those molecules
to make better and more precise

(32:40):
therapeutics, Mh. Better drugs.
So the villains that
you mentioned in today's society
turns out that
ara acid, which controls
the bios
of
pros,
and,
and it was well appreciated that the pros

(33:01):
play important roles in initiating
inflammation.
All the signs we mentioned, heat, swelling,
pain.
These are all
mediated by pros.
Well, in the resolution phase
when the lu
infiltration reaches a maximum.

(33:23):
The resolution program kicks in, and that's where
on
serendipity
comes in, and we found in
mouse models that the precursor
of the pro resolving signals,
the chemical mediator that orchestrate
resolution
come from

(33:45):
the omega 3 essential fatty acids.
Essential because we do not meet
Epa or Dha
We need to take these in in our
diet in our nutrition. And as you know,
these are the major fatty acids that are
present in marine oils.
And it had been known for quite some

(34:05):
time
that the marine oils could reduce
inflammation but the mechanisms
of how that occurred is argued about in
literature and not very clear. So in a
nutshell, what we learned is that the
omega 3 fatty acids that we take in

(34:25):
in our diet. In our daily nutrition set
us up for
self limited
resolution. We are challenged
everyday hundreds
and thousands of times,
the alarm rings
for our defense mechanisms
are white blood cells to come out and

(34:46):
protect us in tissue, and that's when we
need to
turn off that response
and that's where
nutrition plays in a a very important role
in enabling us to have
self limited
inflammation and return to
homeostasis.

(35:06):
That's an excellent
explanation. And I think it it really hit
all the big points. A key development in
your research on inflammation turned out to be
a trip to Asia where unfortunately, you developed
a hole in your intestine. Now that had
to be pretty traumatic and does not sound
like a fun time. Can you tell us

(35:27):
about this incident and it's aftermath, which I
understand gave you a first handy experience and
why controlling
inflammation is important.
Yeah.
Okay. I
was returning from
Japan, and
I thought that I had horrible jet lag.

(35:47):
But it turns out that I couldn't stand
and
I still made it to the lab that
day, but my wife urged me she said,
no. Something's wrong.
You have to go to the.
And the bottom line is that I had
per my bow and I had
peri

(36:07):
brewing, which as you know, is life threatening.
And in the,
some
students that were in my classes...
I said, don't worry about this. This is...
I'm just having a kidney new stone. Yeah.
It's a lot of pain, but it go
away. And that was not it at all.

(36:28):
I went up for emergency surgery,
and
I had a cl
and that taught me
that I couldn't waste any time
that we had to under understand how the
body controlled
inflammation. It was a very unpleasant experience

(36:48):
to me, but I learned a lot and
started to collaborate with Gi pathologist,
James Made and his group used an expert
on epic Gi epithelial cells, and we started
to do the first experiments on how
neutrophils
talk to

(37:08):
epithelial cells and how that acute inflammatory response
can get out of control. When I got
back to the lab,
I said, oh, we have to study peri.
So I switched my
research program,
and I primarily in an in vitro guy.

(37:29):
I like do experiments
in test tubes.
But it became painfully evident that I needed
to bring in animal models.
And so it is then that we started
to study animal models of peri
and self limiting peri
gave birth to the resolve.

(37:52):
In other words.
Yeah. How
that
inflammation in the peri
resolve
was
dictated by
the availability of Epa and Dha
in the system. And to me, this was
revelation.
Because I didn't think much of the literature

(38:13):
at that time around Eb epa and Dha
But clearly, there was an an important role
for these essential fatty acids
in
the human development, and it became my mission
to figure out how they played a role
in
enabling
the bios

(38:34):
of the resolve and the other specialized pro
solving mediator
for protect
and
the macro
derived mediator
of
resolution that we named the maurice.
And I'm happy to report that
the maurice
at least
mar 1, the first reason we discovered

(38:56):
is very potent in controlling pain and tissue
regeneration. And it is in clinical development,
and hopefully that company will be in clinical
trials
for reducing pain
later this year and resolve an e 1
is in clinical trials
this year from another company

(39:19):
and I hope that those companies are successful
because they will bring the first precision tools
to the clinic for
controlling
inflammation? Now
why is this so important? Well,
because
our current
pharma
while adequate in most cases

(39:42):
blocking the
initiation of
inflammation the thinking was, oh, there's just too
many prone inflammatory molecules. We need to reduce
them actually leads to
a
unhealthy state of immune suppression? And why is
that important
because I
1 would be treating rheumatoid arthritis with an

(40:05):
agent that would block a cytokine
or, like, tn alpha,
would open up the system
for
rampant
infection.
So that's a really unwanted side effect.
You wouldn't wanna get Tv as a result
of taking care of your Ra.
So

(40:25):
we think that pro
resolution pharmacology
will pave the way to
developing
a whole new set of precision tools
for clinicians, And it's also opens up an
opportunity
to
think about
precision nutrition and and how can we get

(40:46):
the right amount of Epa and Dha
in our children in our daily diets.
So that we are resilient to the many
challenges that come to us each day as
humans.
When you had your
issues with the peri,
were were you taking any anti inflammatory

(41:06):
medications, non?
Oh, non steroid
no. I
refrain from that, but the main staple treatment
prior to surgery.
Was to be on steroids.
So steroids also
as good as they are in controlling
inflammation. They also lead us to a state

(41:29):
of
immune suppression. It's all about the timing
And
at certain doses,
all of a words his group in Germany
showed that
steroids
like that
can actually turn on
Sp production. So it's a matter of timing
when and how much to use.

(41:51):
And that's a very exciting work.
With these non str,
they typically will will block, obviously, the production
of things like pros land and so they
they alleviate pain, but that's basically but then
the, you know, that's been the focus within
sports medicine community and and a lot of
the areas where I'm working, but I... You

(42:11):
know, obviously, the comp complications, but those are
significant. And I think this is a huge
piece of the problem. Can you explain briefly
what the anti inflammatory
medications will do to the healing process?
Sure. 1 of the big surprises for us.
It was to find that if we added
a non steroid
into

(42:31):
an acute inflammatory
response,
either in the peri
or in the lung and an animal model,
then non steroid,
of course,
reduces pros land,
in some cases down to 0
production, but this un couples
resolution.

(42:52):
And
we need a little bit of pros land
in e e2 to actually trigger
the production of the bio synthetic
enzymes that are needed to make the pro
resolving mediator.
So it's again, it's a
situation of
temporal analysis and when and where? So when

(43:13):
we published those results,
they were replicated by
many on the groups
and working in the areas of
rheumatoid arthritis
and
pulmonary
inflammation, doc levi group,
but there was 1
very
rapid
translation to humans

(43:35):
by
James
Mark worth. And at the time, he working
in
New Zealand,
and he's an exercise ph anesthesiologist
And as you said, in the sports arena,
and
this is unfortunate
in the high schools and all of our
children
have been avid athletes.

(43:56):
Somehow, they have the notion that if they
load up on non steer
before to meet or before
to game
before a match
that this is gonna help them. In fact,
that's not the case. At all. It's the
most delete
thing that we can do. We actually consider
and to push this point of introduce the

(44:19):
notion that non steroid and inflammatory drugs as
the call today are resolution toxic.
And so in James Mark ward study, he
studied 60
males
before and after strenuous
exercise
and he was able to replicate our results
from the animal models in humans and show

(44:41):
that the nsa un uncovered
resolution.
Let me just tell you 1 exciting thing
that's happened from that work that I think
is relevant to all those listening who
loves to play sports.
It turns out that the Sp are made
to bind muscle tissue, not just le sites.

(45:03):
And that the
Sp stimulate the muscle stem cells and a
group in Canada
discovered recently that 1 of the resolve resolve
d 2 stimulated
the
proliferation of muscle cells from stem cell, and
they have reported that thereafter after

(45:24):
trying to treat Du
muscular dystrophy
with resolve and and resolve like agnes
would be
that's exciting.
Yeah. And you... You... Also, when I was
up at the conference that you had up
Harvard, they discussed aging in animals and the
lack of ability to produce resolution media leading

(45:45):
to loss of muscle mass at as we
age.
Yeah. Well, thank you, David for bringing up
that point because it enables me to talk
about Hilda ana.
Who was a fellow in my lamp from
Iceland.
She was the first
nutritional I epidemiologist to join the group, and
she did that study we looked at the

(46:09):
Nih aged mice versus
young mice and found that there was a
defect in the production of resolution mediator,
and I'm happy to make that point because
hilda and athlete
she was training last year and running,
and she had a cardiac event and early

(46:31):
morning run and no 1 was around to
help her, and, unfortunately,
she passed away too soon. So
So that research that she did Yes. It's
a big loss for us.
On the field,
and she just a wonderful investigator
and a

(46:51):
really nice person to work with.
Yeah. And I'm quite a loss.
I'm happy that others
have taken up the
the aging issue and other labs are focused
on on
that research.
But we can thank her for starting that
we're

(47:11):
indeed, and that's so important as the percentage
of the population that's moved into their later
years is grown just immensely. That focus, I
think will continue to be very important.
Stem talk is an educational service of the

(47:33):
Florida Institute for human and machine cognition. A
not for profit research
organization
investigating a broad range of topics,
aimed at understanding and extending human cognition
lo motion, health span,
resilience
and performance.

(48:09):
As we discussed earlier,
and
you know, we just chatted informally about how
uncontrolled inflammation is a very prominent component of
many, many,
unfortunately,
common diseases. We talked about arthritis and we'll
talk in in the future I think about
peri
disease, but asthma, cancer diabetes,

(48:30):
just the whole slew of them including Alzheimer's,
Parkinson's a lot. And so as we think
about and the effect
inflammation on most of the dreaded chronic diseases.
You know, 1 starts to think that there
must be many many therapeutic
opportunities for Pms of various kinds. Can you
talk about what seems to be an explosion

(48:52):
of research in the field in recent years?
It seems to have really garnered much more
interest than in the past. Could you talk
a little bit about that?
Sure,
well,
like all science
it was lonely in the beginning,
but yesterday
on pub med dot gov,
just on the resolve of 1784

(49:16):
publications. Yeah.
That from groups around the world
sure. That constitutes an an explosion,
but there are 2 things going on simultaneously.
1 is increased rec mission that
uncontrolled
inflammation is important in many, many diseases as
you point out, but the other good fortune

(49:38):
for us in the resolution field is that
several companies
have made
the resolve and the specialized pro resolving mediator
available for research use. We published the first
total organic synthesis of each of the molecules
to establish their complete stereo chemistry

(49:59):
and
confirm how they were. But without having
commercial sources so that groups in Taiwan
and groups in Japan and groups in Australia
could purchase the molecules
for example, and all throughout Europe to test
in their systems and make new discoveries and

(50:21):
teach us
how important
stimulating
resolution is.
So
1 of the points I wanna make to
you and to your audience is that this
is such an exciting system because it's a
feed forward system.
We learned that if we give Sp

(50:41):
back in a disease model, not only do
they control
the
inflammation, but they also stimulate
and endogenous programs
to stimulate
more production
of pro resolving mediator
and reduce

(51:01):
inflammation to get to a new
homeostasis.
You've mentioned kind of the super families you
have resolve protect and.
Can you kinda give us a little bit
of an overview of the differences
between those and then maybe the timing that
they might show up in a healing response?
Sure. The first on the scene, if we're

(51:23):
doing a temporal analysis
of p
the
initiation begins
the pro inflammatory media is the pros land
come into play, the cytokines
chemo
come into play. And you heard about them
in the
during Covid because that is the cytokine

(51:45):
storm that brings the lung down and
sound many
individuals during that pandemic.
We then shift to production of the toxins
and they produced from a ara acid
just as
the pros land endo the le.
And then

(52:06):
the system begins to use
Epa and Dha
to make
resolve,
protect,
and then
late in inflammation when the pro resolving macrophages
has come along
as they were described by Mitch Mc
back in early 19 hundreds, the big eaters

(52:29):
they eat the dead neutrophils
that have lost their lives in the battle
against bacteria or in
clearing debris, they need to be cleared.
So that temporal sequence
is what happens in ideal
resolution in a laboratory setting.

(52:50):
They're each
structurally different. So the
Epa derived
resolve
come from
Eva epa, which is a carbon 20 structure
with 5 un saturated double bonds, and we
work out the structures of each of the
resolve
of the E series and 1

(53:11):
that we discovered just
in the beginning of the pandemic is resolving
e 4 number 4 in the panel.
And this molecule
is important in
instructing
the macrophages
in the spleen
to clear
old
red blood cells,

(53:33):
So this is a ph physiological mechanism
that's not necessarily evo
by an acute
inflammatory stimulus.
U.
So there are ph physiological rules, not just
path
rules of the resolve.
The next
structures to come along with the protect and

(53:54):
the protect are trying,
and they are also produced
from
Omega
3 central fatty acids, but here this... The
precursor is Dha.
And then the D series resolve kicking,
and they're the base structure old Dha in
each molecule of the D series

(54:16):
we
carried out the structural
motivation of, and they each
activate different receptors.
Holy cow. We have
receptors for each of the major families,
and those receptors stimulate
resolution.
1 of the really exciting things that's come
off. Well, I'm excited about it is that

(54:37):
a a company in France
has followed all our were on resolution, Os,
they made an agonist
antibody. An antibody
that will
activate the resolve an e 1 receptor,
and they demonstrated
that that antibody can help in cancer

(54:58):
models in reducing pain
and reducing
inflammation? Now why is that so exciting, Trolley?
Well. The big pushback for me in trying
to make my medics
with companies
has been the enormous cost of making the
scale up of these what seem like

(55:20):
simple molecules,
but they actually quite difficult to s In
some cases, the steps are 22
steps
So that makes
manufacturing of the molecule by total organic synthesis,
very, very challenging and very costly
Now I never thought that cost is gonna
matter when it's gonna improve life. But as

(55:43):
you know, that's a little naive, and that's
what companies
live by is being able to make a
profit.
So that's why I'm so happy to see
agonist
antibodies emerge
as a wait to stimulate
resolution.
I think it'll change health care completely honestly.
Yes. I agree as well. In fact, far

(56:05):
our listeners, I think I I'd like to
mention an article that you did back in
20 17 that I particularly liked. It was
in the journal of my molecular aspects of
medicine. It was sort of like a an
overall review sort of thing. It was really
excellent, and it talked about Sp marking the
dawn of resolution because theology and pharmacology,
and it was it was a really good

(56:27):
overview article. We'll provide a link in the
show notes, to the article for the listeners
so they can read it as well.
Oh, good. So happy that you liked that.
You know, that was really
can a a tribute to my colleagues and
students and fellows.

(56:47):
That have worked with me over the years.
That was a special issue of the journal
molecular aspects with medicine
Is that 1 of my former of fellows,
who's a professor in the Uk talked to
Jasmine Dolly, edited the the series. And there
are articles
in there by all our colleagues and form

(57:09):
students. But in the review that... It's basically
a preface to those chapters in the special
issue. And III tried to hit the high
points.
And as I recall, I discussed in the
introduction, Claude Bernard
because
Claude Bernard was...
Very

(57:30):
influential and my learning
about biomedical sciences, and he wrote The study
of experimental medicine.
Introduction to the study of experimental medicine in
18 65.
Wow. And in that
book,
he
describes
that each of the disciplines,

(57:51):
the dawn of
physiology and pathology
and chemistry, each develop as separate disciplines.
Any urged us to have inter
discussions.
And that's, I'd have to say is the
hallmark of my research
is it's a multi disciplinary approach,

(58:13):
chemistry,
cell biology,
pathology,
interacting with different
disciplines,
internal medicine,
surgery
and learning their perspective
in oral medicine,
peri
disease you mentioned, and I learned from them
all and we work together on this common

(58:37):
mission, which is our mantra.
We repeat in my lab meeting every week,
our mission is to help us many people
as we can. Mh So
I also
in that short
article
focused
in on the importance of Luca site traffic

(58:58):
and this repertoire of edema
ne
infiltration and the non
recruitment of mono site in macrophages,
which is
the acute inflammatory
response
now people get that confused with acute
inflammation, and

(59:18):
I think medical school is so jammed with
so much to learn.
That people
don't have an opportunity to recall
this chapter 3
in Robinson and Cor
on
inflammation, and I urge all the medical students
saying graduate students and clinicians out there, dust

(59:39):
off fear Robinson and Kat
and
take a look at that chapter. And I
was very fortunate to work with professor C,
this the chair of pathology here,
and
he was very, very
instrumental
in my career development.
And I have to say that I've been

(59:59):
fortunate with mentors,
but every academic mission needs just not 1
mental mentor, but
half a dozen mentors
as we take this journey.
I think
we too often hear that epidemic tale of
1 giant mentor, but we all stand on
the shoulders of multiple giants if we're going

(01:00:20):
to be successful.
Absolutely. I I use
the things that you've been teaching every day
in my practice and working with teams and
athletes and veterans,
I mean, this has made such an impact
on on their lives. I wonder if if
we can take just a
simplistic
sort of for for some of our audience

(01:00:40):
that aren't as scientifically
minded or their background maybe makes it a
little bit confusing. 1 of the ways that
I described this in terms of how I
discuss this with an athlete, the difference between
inflammation and resolution. If I am
I, I'm 5 1180
pounds. So... And and I'm in my fifties.
I shouldn't be playing any professional sport. But

(01:01:01):
if I for some reason, get stuck on
a pitching mound for a professional baseball team
as a joke. It wouldn't take a more
than 1 or 2 pitches to figure out
that I'm a mistake.
So getting me off the field is sort
of what I described to the athlete as
the inflammatory phase, an excessive inflammation would be
pulling more than me off the field, either
way you look at we're gonna lose until

(01:01:22):
you get a replacement. Is that inaccurate or
or somewhat maybe useful way of describing this
in terms of the difference between inflammation resolution
and how it affects people?
Yeah. I think that's a great analogy
because it's important to
provide mental images to people
that they can relate to if you're speaking

(01:01:44):
to an athlete
a baseball player, that's very, very appropriate. If
you're speaking to a surgeon and, I don't
think so.
Absolutely.
They're won't very far. Yeah.
No but search gets it why
we need to control

(01:02:04):
inflammation and
certainly,
the critical care docs get why we need
to understand what's going on in sepsis.
1 of the other
things we introduce
is this concept of an I immune resolve
and rather than a blocking
agent that we would have an agent

(01:02:25):
as a therapeutic that would stimulate the body's
own
ability to resolve. And we came up with
that by doing
in the laboratory,
the first
quantitative
assessments
and introduce some very simple
calculations in a systems approach to

(01:02:46):
studying how plus resolves.
And
there was 1 review that doctor
of M Per already did for
children,
which I thought was really cute in the
frontiers
of
immunology.
He
published

(01:03:06):
resolution for kids. And,
yeah, it's worth looking at
It sounds really interesting.
Charles, let's talk about some of your more
recent research at d
laboratory
Can you give us an overview of the
research currently
underway in the lab?
Well, we have

(01:03:27):
ongoing
studies
detailing the
bios
of
resolve.
Working out the complete stereo chemistry of transient
intermediates, which is really challenging.
And then other studies that are going on
in the lab that are
addressing
how to activate

(01:03:49):
resolution
during
infection and how to clear
infectious
inflammation. And then we have ongoing
collaborations with Doctor Levi laboratory
looking at the impacts of environmental
triggers
environmental
agents on the resolution and how they cause

(01:04:13):
inflammation. And 1 of the very exciting projects
we just got funded from Nih is with
a cancer researcher or deepak Pan
at the
hospital
cancer expert looking at how
to stimulate
resolution of inflammation around solid tumors
to
reduce the tumor burden, and those are so

(01:04:35):
exciting.
Keeps me happy
coming into work every day.
So that's roughly
what we have going on
at this time. And I I should say
that I'm
very, very fortunate
to be a Grant
of the National Institute of General Medicine,

(01:04:57):
helped us enormously
because the base were of
resolution and working out the bios
of each of the members of the super
family of pre resolving media was supported by
a program project grant that I led for
10 years
that was supported by N gm, and I've

(01:05:20):
been
supported by Gm
from my entire Career. The other institute that's
really been
incredibly important is
C in developing this work. And there I
served as a principal investigator,
program director
for a p 50 cent grant where we

(01:05:41):
used peri
disease as a
demonstration of controlling
inflammation.
That's about it. Yeah. So last year, you
had another article on the proceedings of National
Academy of sciences that was titled resolve and
d 1 prevents in j
swarming and transplant lungs. And this this provided

(01:06:03):
some insights for therapeutic enhancing per resolution pathways
to minimize early le sight mediated tissue injury
and promote healing following
transplantation. Can you talk about the
progression in that field?
And how this impacts us?
Sure.
I really
love this study
because
in the Or,

(01:06:24):
and particularly in transplant,
there's a phenomenon called ref low injury. Where
a surgeon when the clamp a vessel to
work in an in an area to repair
it. When they open the clamp the
sites that come rushing out in the blood.
They
have become preemptively

(01:06:47):
activated and they hit that lung
and start to cause collateral tissue damage.
And the reason why I like this study
with Daniel in his group so much is
that they have a tool photon microscope
and it's possible to visualize
what's going on during this ref flow injury.

(01:07:10):
So first, in in humans, we were able
to get
from
Daniel and his colleagues, human graphs and analyze
them using
Lc cns sms, and we could
follow the temporal
production of
the pros land,
luca
and
the resolve.

(01:07:31):
In this primary graph
dysfunction. And then going to
the animal model where it can do
real time movies,
doctor Lee and his group has made these
extraordinary movies
using dual photon microscopy,
of the lung where you could see the

(01:07:54):
neutrophils
swarming.
I urge everyone to to just common
take a look at those movies, they're available
on the P
website. And what's so
convincing and so dramatic as when giving
resolve in d 1,
it stops the swarm

(01:08:16):
you can see
that it stops the swarming over the le
sites and prevents
collateral tissue damage
and you can visualize all this
in that study. And the the reason why
I like it so much is because
this is the primary
action
of the resolve

(01:08:37):
when they are produced
to control
excessive
site traffic.
Does this translate over into
areas such as, an ischemic stroke or ischemic
my cardi after cardiovascular or disease event? Absolutely.
These
cellular molecular events, huge translate

(01:08:58):
to cardiovascular
disease. Organ transplant
is
a major major issue where we see all
these things happening, but in atherosclerosis atherosclerosis in
cardiovascular
disease, these are happening over a long period
of time, decades in some cases, the vascular
endo epithelium and surrounding tissues become inflamed

(01:09:22):
And there's a very nice war in the
area of atherosclerosis some cardiovascular
disease being done by a number of groups
1 is talked Gabby Fred crew at albany
Medical. He's a former of member of my
crew. And Magnus Beck,
a cardiologist a Carolyn
institute, and he's working in this area, and

(01:09:45):
they have published some really elegant studies demonstrating
how resolve can reduce the
sequel of
inflammation and as sclerosis in cardiovascular
disease. I was very fortunate some years ago
back in 2006
in 2007

(01:10:05):
to work with Larry Chan is an endo
knowledge at Baylor and Larry was able to
make in a rabbit, a trans
rabbit
that over produced the enzyme that's responsible for
Lip fox and resolve
production. And 1 of the things we were

(01:10:25):
saw is that
those rabbits
didn't get
atherosclerosis
and
they had a very
diminished
acute inflammatory
response in skin on challenge They were, like
super rabbits.
Lucky rabbits, I guess. Yeah. And the reason
why I mentioned the rabbit is because much

(01:10:46):
of what's known about the path biology.
Of
atherosclerosis
comes from the Watt knob rabbit model. Mh.
Where
taking a high
lipid cholesterol
intake leads to an
plaque and those rabbits. And the cool thing
is that my colleagues and I was not

(01:11:08):
involved in this study
when they treated
the
rabbits para
that had
inflammation, they did not
get any
atherosclerosis atherosclerosis.
The vessels will clean. It just amazing. That's
Tom Van dyke group working with another

(01:11:29):
imaging specialists in the area of lipids at
d you. Jim Hamilton. Nice study.
So we will put a link in the
show notes to Gabriel Fred article that you
mentioned, looking at the evidence that supports
Sp as therapeutic tools for the treatment of
Arthur Squad a cardiovascular
disease sometime in the future. That leads to

(01:11:50):
a sort of a follow up question here.
You mentioned rabbits, and that research is is
very interesting. That, you know, the natural diet
for a rabbit isn't very much like a
natural diet for humans I would assert. But
in any case, What I'd really be interested
in, are there any clinical trials
in the works that you know of that
will test whether increasing Sp in vivo in

(01:12:11):
humans.
Can indeed affect art
progression. I think that would be really fascinating.
Yeah. You're absolutely right, Ken
that is a tall order. That's a very
expensive
long
type of study to do, but nonetheless,
it is extremely important. And Magnus beck the

(01:12:32):
cardiologist that I mentioned at Car institute, he
was able to secure. A ground from the
Eu
across multiple
countries where they are going to be testing
exactly that and I'm fortunate to be a
member of their scientific advisory
and watching how the data comes in and

(01:12:53):
I I do believe that they will be
successful
Because these mechanisms
are highly,
conserve the cross species all the way from
fish to human.
It's really interesting and very hopeful for the
outcome of that study.
Charles, you have 2 children who are currently

(01:13:13):
in the military. And your third is
potentially on the way into the military. What
are your thought on a need for the
use of Sp in the military population.
That's a very deep question, David. And because
I'm... It's emotionally tied to trying to do
research that will be helpful
in the battlefield and say, well. Where did

(01:13:35):
you get that?
Idea from. So well,
I was invited to the San Antonio
Battlefield
research sent
a few years back to give the Bass
pruitt
lecture and doctor Pruitt was a trauma surgeon
the military. And on that occasion, I got

(01:13:56):
a chance to see some of the very
important work that they're doing at that site,
and started a
collaboration with the Doctor rios on using
some of the Sp, I mean they're a
synthetic form to protect
ear damage from acoustic injury, and
he has

(01:14:16):
developed a model for blast injury, And what
happens in the battlefield is instead of a
soldier steps on a
explosive device the day after
perhaps
losing a limb, those soldiers
lose sight due to a retinal detachment from

(01:14:36):
the blast shock and
1 of the Sp
neuro protect and dew 1 protects
from that and animal models.
Retinal detachment. And I I didn't have an
opportunity to tell you, but the neuro
are produced and the retinal pigment
epithelial cells. That's 1 of the places that

(01:14:58):
make that specific Spf. So I'm hoping that
we can get some of those molecules
into the battlefield kit. And then the other
approach, which I think is so vital is
would many have called
nutritional armor to help increase the resilience

(01:15:19):
in the battlefield
by
specific
support of the Sp system? I say, well,
how are you gonna do actual? Well, since
it's taken
more than a lifetime
to
make mime
and to launch
the idea of precision
therapeutics in
resolution,

(01:15:39):
resolution pharmacology.
1 of the really
fortunate
things we stumbled into is that marine organisms
not only make
And Dha
they also fake
resolve,
and they make them in high amounts. So
it turns out that when you purchase

(01:16:00):
at the local store, your omega 3. Fatty
acids most of them come from the Peruvian
ant anchovy So Anchovies very rich in Epa
and Dha so you wanna get anchovies on
your pizza. But the cool thing is that
they're very rich.
Anchovies and the intermediates in the bios

(01:16:21):
of resolve. So why is that important? Because
if you
give the intermediate resolve,
they're used at about a hundred times
more
efficacious than Epa and Dha.
And then,
we thought that they were only
bios synthetic intermediates. It turns out that they

(01:16:42):
also carry potent biological
actions, 17,
1 of the molecules we described is very
potent in regulating
pain,
and 18 e, which is an intermediate e
series bios
of res
is very potent in regulating

(01:17:03):
cardiovascular
function.
So do you see in Au
situations, let's say, pilots or, you know, other
extreme environments do you see a preventative aspect
that may be used from, let's say, taking
Sp over the counter?
Yes. They would absolutely
I do hope that this is the direction
that I'm having a greater visibility

(01:17:24):
to
larger your audience
what should give me an opportunity to do
today will dawn all people that this is
really preventative medicine. And that if we use
precision nutrition, we could raise
our
resilience.
And, yes. And then to use the therapeutic
approaches more and more

(01:17:46):
extreme cases.
You mentioned a phrase
nutritional armor earlier. And Joel Hi is 1
of the people that coined that, and I
remember he visited here and gave a lecture
back in 24 team about nutritional armor and
he was stressing the importance of fish oils
and related substances. So I I hope he's

(01:18:08):
been tracking your work since then, because I'm
sure he would find it really interesting.
I know Joe Well, he was an Nih
and
I was on the board of scientific
advisors
at the Institute he worked in which was
n anti triple
And he was a student of Norman salem

(01:18:30):
and Norman has done some of the most
impactful work
in
thinking about Epa and Dha in nutrition. And
he's demonstrated how important and his team how
important Dha is in neural development. Yes. So
we don't, Joe. Sure. Joe is a psychiatrist
by training and he been aware of, the

(01:18:53):
importance of
omega 3 in the diet and preventing
suicide. Yes. Partly,
due to my interactions with him. At the
time was on the defense science board, and,
of course, the issues having to do with
injury brain injury, but also suicidal dial were
issues for the board. And in 1 of

(01:19:14):
the reports, it talks about, there should be
more focused on nutritional armor and on thinking
about Dha and other kinds of approaches. And
so it it was very hard to get
it in the report because defense science board
reports are normally dominated
by things based in physics or things or
computer science or, you know, not something biological.

(01:19:36):
And so it was interesting process.
What I can tell you is that there
been some very nice studies in Tb,
the traumatic brain injury that was done by
initially by the
research center in
Kentucky

(01:19:56):
for
Tb. And they showed that in repetitive Tb,
a
per progressive model in animals that
resolve,
E1D1D2
all protect from
Tb. And
that's
an issue that also crosses over not just

(01:20:19):
from the battlefield
but also
into
sports today. Absolutely.
That work
stimulated
others in the area of Alzheimer's,
and neuroscientist
to look at, how the Sp,
regulate and protect in neuro

(01:20:39):
inflammation inflammation. And there,
we had shown very early on that micro
cells a brain micro cells make resolve,
and those cells are like
the macrophages
of peripheral blood, and they're the ones that
are thought to
be in an excessive pro inflammatory

(01:21:01):
state in disease like.
And just yesterday, I read a paper from
the Car group group, the neuroscience group working
on
Alzheimer's and how they used Mar 1, 1
of the Sp to
protect
from
advancement of Alzheimer's deceased.

(01:21:21):
That's Mary Sc group. And they also did
a very cool study that came out just
about a year and a half ago where
they gave
Sp
intra in the mouse and it was in
an alzheimer's mouse, and they found that those
mice
got their memory back in my base studies.

(01:21:43):
Really impressive and reduced the neural
inflammation. And 1 other line of research, which
I think is very important. That's come up
from Japan
about,
Sp is that they may actually be
the molecules
themselves and endogenous
antidepressants.
Mh. That is interesting.

(01:22:05):
In the sports world, there's a big focus
on recovery and healing because the high number
of injuries and nagging chronic mu
problems. Does it make sense to focus more
on resolution in this context rather than thinking
sort of anti inflammatory in the traditional or
old sense of understanding.
Yes, David. This is something we need to
pound the table

(01:22:27):
about because traditional anti inflammatory therapies
delay wound healing.
That's 1 of the unwanted side effects.
But the natural progression of
resolution back to homeostasis is tissue
regeneration. And
we have found that there are

(01:22:48):
additional molecules
that are produced during the resolution phase
by the Sv sp pathways
that stimulate
tissue
regeneration. And we found that in a very
cool system
in p area. If we cut p area
in half, this little worm will grow back
both halves

(01:23:09):
in, like, 5 to 7 days. But if
we added 1 of these
molecules that we isolated
from
resolution phase and then determined its structure, we
could shorten
that
regeneration period. So tissue
regeneration is part of the resolution cascade, the

(01:23:32):
resolution code.
And a follow up to that, at your
conference, I noticed there were several
papers discussing
sleep and how resolution and sleep kind of
interact or what the what the play is.
Do you mind touching on that as well?
Sure. The sleep group is over at the
Bi,
and Monica hack is the senior

(01:23:54):
there and
I just serve as a
mentor to the fellow that presented. She showed
disrupted sleep study And in disruptive sleep,
the pro inflammatory
media just go up in peripheral blood. And
there's a deficit
of

(01:24:15):
Sp.
So I was quite surprised to see that
and those analyses were
done by the group in Michigan,
and it really suggests that
that to get
full sleep cycle
1 has to over
inflammation. So there, I think the Sp could

(01:24:36):
have a a real
therapeutic
impact in enabling people to
skip over, if you will,
disrupt sleep pattern.
And I think that could have enormous impact
in the general public
in
military and
in sports world as well.

(01:24:57):
Yeah. I I see in the professional sports
world, but also with friends of mine that
are
you know, either either vet veterans or, active
duty population, in fact of a friend that
is involved in human performance based, active duty
and He does some...
He's in the reserves as well, but 1
1 of the things that he told me
recently is since he started taking these Sp,

(01:25:18):
he sleeps better. In his forties now, he
is getting better times on a lot of
his physical testing that he was getting when
he was in his twenties. So it's having
huge. And that's the only change that he's
made. And I see that across the board
when I'm dealing with athletes that those kind
of improvements. It's really outstanding.
On a personal note, I've been taking Sp
for a long time.

(01:25:39):
Don't even remember how long, but quite a
while, in particular, the pro resolving. I think
it's called That pro resolve. Yeah. Pro resolve.
And the other 1 is Meta
active. Sp active yeah 2 that
that I personally
take?
Well, you'll be happy to know that they
are the same pill

(01:25:59):
sold by very happy.
The
actually, I'll say a little anecdote there. You
know, to sort of jump start that getting
it to humans
I gave the Spanish company
Biotech that had this,
and and this is actually an important point
for your audience.
Okay. So

(01:26:20):
supplements, do we really need supplements?
Well, if you're eating a well balanced diet,
maybe not? So some supplements
are
synthetic molecules
like vitamin C, b 12, etcetera, and that's
definitely needed. In the case of
of the Sp active,

(01:26:40):
those are
the natural
Sp
isolated
from Peruvian
and Anchovies. And the silo
corporation had
at that time,
around
20 12, the world's
patent in dominating
what's called C 2 based

(01:27:01):
purification. So there was no
organics that would ever touch, no solvent, the
molecules
And so as I mentioned briefly earlier, we
found that the peruvian trophy ads
Sp and the intermediates Sp and I obtained
the patent on that, which I gave to

(01:27:22):
the Biotech group for 1 dollar why.
Because I wanted to see
this get to people as fast as possible.
And if they did that, I'm so happy
they did and their first customers were meta
and meta
that has
done and is doing
a wonderful job in making

(01:27:43):
educational material available
about Sp
and doing nice clinical studies showing that taking
the Sp act reduces pain
and having those tools available for people like
Doctor Le,
this opens up even more
potential uses

(01:28:04):
because it's only until you get a tool
in a physician's hand until you really know
where things are good for. Yeah. Does that
make sense? Absolutely Sure certainly does from my
perspective. Yeah. I totally agree with you? Yeah.
So very soon
you'll be teaching us what we really need
to do with the Sp active. The... And

(01:28:25):
I'll tell you a story that that makes
me... That there are 2 things. You know,
I you must heard in what I'm saying
that my basis is really in molecular pharmacology,
you know, that I love that stuff. So
the first is
the discovery of the viagra molecules. Okay. This...
You know, no 1 went out to specifically

(01:28:46):
discover something for Ed.
This was a side effect of a a
cardiovascular
program
that pfizer had to block pho,
and it turned out that their molecule
block
that's it. That regulates a cyclic Gmt

(01:29:09):
and
and and relieve...
I'm, I'm trying to figure out a delicate
way to say this.
But yeah Yeah.
Dysfunction
Ed.
Okay? Then this is a
a really important problem. The other 1, which
is really cool is
Lu,

(01:29:30):
which is used. It's a it's an eye
drop to lower
intra pressure. It's actually across the land and
my medicare analog that was developed by
Astra.
And
when that
compound went into use.
The side effect noted by the op

(01:29:50):
was sent, people got extra long eyelashes
It was a side effect, and the other
side effect was it turn brown eyes blue.
Oh, wow.
So
you can imagine there's a need for both
of those, and so businesses has grown up

(01:30:10):
where companies make the compound and put it
in cosmetics
for
people who like to have low eyelashes. So
I I'm anticipating
that
just like we learned,
and I didn't anticipate it. I didn't even
expect it that muscle was gonna make
Sp.

(01:30:32):
When we found that adipose
tissue, fat made
pro inflammatory mediator and the Sp
were pretty shocked
at that. So I think there are some
unexpected things to come up both in the
clinical
observations and our
continuation of these

(01:30:53):
investigations is gonna teach us
how to
use
this information in the best way pops sold
to help as many people as possible. Yeah.
Be great.
Looping back to the early days of your
career. I just wanna tie back to that
little bit because Stem talk has many, many
listeners

(01:31:13):
in graduate and medical school. So we get
a lot of correspondence
from med students in graduate students and physicians
as well. But we're really very interested in
these young budding scientists and and physicians. And
you know, they they have a lot of
passion.
I understand there were 2 books that you
read earlier in your career that really had

(01:31:34):
a big impact on you, and maybe we...
Maybe we should share this with
with these folks. 1 was the art of
scientific
investigation? And I understand the other was men
like gods. What stood out about these books
and would you still recommend them to young
investigators and graduate students and medical students today.
Yes. Wow. That's a great question. Thank you.

(01:31:57):
So the auto scientific
investigation by beverage.
I still ask people to take a look
at it. Beverages is a professor
of Pathology, at University at Cambridge, and this
is the only book I know
that tries to
operationalize
preparing to do research. And in the first

(01:32:20):
page,
it says
Scientific
research is not itself a science. It is
still an art or a craft. And I
believe that is very true, and
he gives some
inspiring pearls
throughout the book and tells people how to
go about preparing yourself to make discoveries.

(01:32:43):
Yep. I would definitely tell people to go
out and get it It's out of print.
I think the last print thing of it
was in 19 57,
but you can get almost anything today out
there on Amazon. So dude take a look
for it if you're interested in the career
in science, the art of scientific

(01:33:04):
investigation. And what about the other book? Men
like gods. What's that about? Well,
okay.
That That's an h g wells book that
he wrote towards the end of his life
that really into weaves many of the concepts
that he had in his other books, like
time machine and war the worlds. And

(01:33:28):
you can hear, III
like Sci.
I don't have as much time to read
it these days, but men like gods was
particularly,
Interesting to me at the time because it's
a it's about an English
newspaper man who's driving on a road,
mean, this is in the late 19 twenties.

(01:33:50):
And
he and several other,
I would say, representative of
society at that time were transported
to a parallel
universe in time and Earth 3000
years
ahead so.
And

(01:34:10):
and then, you know, this is a Utopian
society
and the main character demons is really enamored
by the whole society,
but they become jeopardize
buy the the viruses
that the
people from an out time brought to them,

(01:34:31):
and so they had to be isolated
on a on an island. So it brings
up a lot of concepts
that like in war of the worlds
H she wells, you know, in the end,
we don't defeat the invaders.
They get defeated by the microbes
of Earth.
I I just

(01:34:51):
I just like those
frames shift
ideas, and I I encourage people to read
not only science
outside of your area of interest, but to
get
stimulation from
other sources from reading books
that you like and from listening to music

(01:35:12):
and
and going out and running and getting your
undo up and smiling every day, the other
book that I thought was... And I think
is very important There were 2 other books.
For the medical students,
the book that was transformative
for me was Arrow Smith. Oh. Yeah. And
and that's not the rock group. It is

(01:35:34):
Sing sinclair Lewis Arrow smith. Yeah. Famous book.
Yeah. It's in and it picks up a
medical student in his early
years and carries him through
the clinical trial
and the forces that come to bear
during
this epidemic that they face. Yeah. I was

(01:35:55):
Saint sinclair Lewis
book and he was the first
literature Nobel Lau from the
in United States. So it's definitely worth reading.
And the other book is an obscure book
that I found that I just love and
I still copy a page from it and
hand it out to members of my crew
during a lab mid and that's Maxwell

(01:36:18):
Malt, MALTZ.
He was a plastic surgeon and he wrote
a book of his experiences,
towards the end of his career that he
called Psycho cyber.
So what is that, troy? Well, this is
where you could program.
He believes the brain was like a computer.

(01:36:39):
You're putting good stuff. You get out good
stuff. And you can program
yourself to be positive and have a positive
impact on those around you. And he learned
this apparently by
performing plastic surgery on people. He noticed that
if someone came to him and said oh,
you know, my ear are too toothpick, you
know, can you can you take off the

(01:37:01):
lopez so. And after he did that in
21 days after the surgery, he noticed that
there was a personality change,
And so he documented
that it wrote this book for us.
Interesting. Yeah. Very. Well Charles, this has been
great fun. And we've enjoyed talking with you
very much, and I'm sure our listeners will

(01:37:21):
as well.
Absolutely. Thank you for joining us today. Keep
up the good work. Yeah. That's for sure.
Well, thank you so much, David and can
for giving me this opportunity to
expose our passions and to
tell people about our mission, and I hope
that others will take it up. And if

(01:37:43):
you're interested,
do right to me may take me a
little time to get back to you, but
I certainly will. Thank you so much, guys.
Well, you're quite welcome, Moe fascinating
interview and thank you for your important work.
Yeah. Thank you very much.
Stem talk done stem dot com. Stem? Talk
stem talk.

(01:38:04):
I'm 1 of those people we talked about
today who finds Sp to be a revolutionary
new field of research. I'm grateful for the
work that Charles has done in pioneering the
potential of Sp to promote the natural termination
of inflammation. In addition to my performance medicine
practice where I see a wide variety of
high performing patients and athletes and retired in
active military members. These patients have inflammation as

(01:38:26):
as a result to persist and injuries and
trauma, I'm a big fan of Sp because
of the positive impact that they have had
on so many of my patients to me.
This
discovery is nobel worthy
information as I believe it will transform health
care in the near future. I suspect, David,
that 1 reason you are particularly fond of
Sp among others is because they allow a

(01:38:47):
person to avoid anti inflammatory drugs and their
numerous side effects. Here at I c, we've
worked a lot with military populations who suffer
inflammation as a result of persistent injuries. So
the potential of Sp to promote the natural
resolution of inflammation is something I am keenly
interested in. As Charles has pointed out in
the past,

(01:39:07):
anti inflammation is not equivalent to pro resolution.
Anti inflammation suggests a blockade of signals and
cells. Whereas pro resolution suggest an activation of
signals and cells quite different. This is David
Lame, signing off for now. And this is
Ken ford saying goodbye until we meet again
on Stem talk.

(01:39:35):
Thank you for listening to Stem talk.
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More information about this, and other episodes can
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There, you can also find more information about

(01:39:56):
the guests we interview.

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Episode 170: Charles Serhan on the use of specialized pro-resolving mediators to resolve inflammation

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