I have had the great privilege of being associated with NIAMS ever since there was a NIAMS.
I came to the NIH in 1985 when the Institute as Steve said before, the NIADDK and the NIDDK
split off from NIAMS, and so I have been here actually
ever since, since the being of the Institute in 1986, and
certainly it has been a wonderful adventure and experience to see the Institute grow in
the ways that it has, both intramurally and extramurally, under
the leadership of Larry Shulman, and Michael Lockshin
and Steve for the last several years, so it's been a wonderful opportunity and a great honor
to be here this morning to speak to you.
In any case, to turn to the topic at hand, we will be speaking, at least a little bit,
I will stay within my time, I have 13 minutes and 46 seconds left
to talk about from base pairs to bedside, adventures in the
genomics of inflammation.
This has been an adventure both for me and for a lot of other people that have gotten
involved in this work.
So as Bob mentioned, in fact, I started in this area of research back in late 1985 when
I saw this patient.
It was a young man of Armenian ancestry who presented in his early 20s with a lifelong
history going back to infancy of episodes of arthritis lasting
on the order of a week at a time, roughly once a month.
So in his 20s, he had already had a couple of hundred such episodes.
And interestingly, during the episodes he would be hobbled, he would have to use a cane
or crutches, but between episodes, he was normal.
When I saw him that day, he didn't have any arthritis, didn't have a limp or fever.
Fortunately it happened that Paul Plotz was my attending on the case and there was a fellow
from Israel in the lab that I was working in who put me
on to the correct diagnosis of Familial Mediterranean Fever.
This was a disease known simply to be a genetic disorder caused by a single recessive gene,
but nobody knew what that gene was or what it did or
even what chromosome it was on.
But this was back at that wonderful time at the beginning, just the very beginning, the
dawn of the Human Genome Project.
So this was the time when positional cloning, that method in which you could recruit a group
of families with a particular disease, if you knew that
it was a single gene disease, you could recruit a group of
families, figure the genetics, and if you didn't know anything about the gene, you could
discover the gene.
And seeing the dramatic inflammatory phenotype this man had, I thought that's for me.
That's what I'm going to do.
And, of course, the naïveté of youth, I thought well, if Francis Collins can do this
for Cystic Fibrosis, Dan Kastner can do it for FMF.
So the adventure was on.
Back in the summer of 1989, I spent the summer in Israel and drew blood from 50 different
families with FMF with multiple members affected with FMF
and some unaffected people as well; 350 samples all
together.
We then did linkage studies and figured out the gene for FMF is on the end of the short
arm of chromosome 16.
Then we became the genome project for that area of chromosome 16 because, at that point,
the genome project hadn't yet born all the fruits
that we enjoy today.
So all of the maps and sequences and the gene annotations and so forth, weren't there, so
we had to make our own maps of that region.
It took us five years from the time we knew what the chromosomal location was to the point
where we had a map of some 200,000 base pairs that
were 10 genes that we discovered in this region.
As luck would have it, it was the 10th of the ten genes that turned out to have mutations
associated with FMF.
That gene encodes a protein that was a positional cloner’s dream.
What is a positional cloner’s dream?
A gene that wasn't known before.
That might tell us something about the mechanism of the disease under study.
This turned out to encode a protein that wasn't in databases and, in fact, we didn't have
a clue at that time as to what it was or exactly how it worked.
But over the course of the last, whatever it is, 14 years, it's become apparent that
the end terminus of this gene encodes a domain known as the pyrin
domain after the name we gave the protein, pyrin that,
in fact, is in some 20 different proteins in the human that are involved in the regulation
of inflammation.
We won't go into the details because I will stick to my time, but, in any case, it is
the case that this protein is involved in the regulation of the
activation of key cytokines and inflammation for interleukin
1.
There are a number of other genes that have this pyrin domain discovered, some of which
actually there are mutations in them that are associated
with human disease and treatments for those other diseases
that are based on intervening to interrupt IL-1 signaling.
In any event, let's fast forward 20 years and let’s get from bad news from Baghdad,
20 years from the time the story started was 2005.
We got a referral of a patient, a young man, from Baghdad, Iraq, via the Mayo Clinic who
had FMF, mutation proven FMF.
He had two copies of the M 694V mutation, a very bad mutation.
And as a complication of FMF, because he had not been on any treatment over the course
of his 18 years of life, he had a deposition of an inflammatory
protein called amyloid.
That protein was in his kidneys causing kidney failure.
It was in his GI tract causing intractable diarrhea and it was in his heart.
In fact, he was in heart failure when he came to the NIH.
I went to a meeting, a meeting – a Gordon conference, a moment you'll never forget where
I got one of the organizers to come up to me after my talk
to say that the ICU at the NIH wanted to talk to me on the
phone.
Sure enough this guy had decompensated; the treatments that usually would be used for
FMF, colchicine couldn't be given because it causes
diarrhea, and he already had intractable diarrhea from
malabsorption from his amyloid, so we treated him with IL-1 inhibitor, anakinra.
This shows his initial experience with that.
When he was on anakinra, his inflammatory markers were
normalized.
When he went off anakinra, because of a line infection, the numbers went back up and
came back down again on anakinra, that has actually led to the resorption of the amyloid
deposits in this young man.
He's had a kidney transplant, but the amyloid in his heart has resorbed to the point where
he's now able to function normally.
In fact, it's resorbed in his GI tract.
Here is a picture of him after having a pizza lunch a year or so ago.
My goodness, there's something that came up, not sure how to get rid of that.
In any case, that's one example of how this can actually help.
Here is another family I'll just briefly mention.
A family I heard about while looking for the gene for FMF.
These people, this family is from Louisiana, not Cajun, but from Cajun country.
The mom Glenda had called me on the phone while we were looking for the gene for FMF,
left a voicemail saying her husband died in a VA
hospital in Louisiana from what was said to be FMF, but she
didn't believe it.
The reason that she didn't believe it was her daughter had the same thing and she had
read that FMF is recessively inherited, so it couldn't be what
her husband died of and what her daughter also had was
FMF.
This is from a lady in the back country of Louisiana that got us interested in this disease,
and here is an image from the cover of Cell, which ultimately
published our findings.
This is the amyloid deposits in the autopsy specimen of the kidney from the father.
In any case, it turns out this family has mutations in the TNF receptor, a different
inflammatory molecule which then leads to different treatment for
the patients rather than the treatments we would use for
FMF.
Another case, there is a quote, I don't speak French, so hopefully this from the Internet
is correct.
Louis Pasteur’s famous comment that chance favors the prepared mind.
So actually a colleague of mine, Raphaela Goldbach-Mansky, was referred to this young
man named Jonathan from North Carolina who was thought
to have systemic onset JIA.
She astutely realized he didn't have that; he had something called NOMID, neonatal onset
multi-system inflammatory disease, where there's inflammation
of the skin, the joints, and central nervous system
that leads to blindness and deafness and mental retardation.
Because of that, we sequenced a particular gene known to be involved in this process
and found a mutation in that gene that's involved in the
regulation of IL-1, as well.
And this led to a clinical trial that Raphaela conducted, which was published in the New
England Journal several years ago, which shows the dramatic
effect of IL-1 inhibitors in these patients.
You can see the rash goes away, the conjunctivitis goes away.
The white represents CNS inflammation, central nervous system inflammation, which
goes away with the IL-1 inhibitor.
Even inflammation with the cochlea shown here with the arrow goes away.
Then finally, a mystery from the Maritime Provinces.
Another patient with the skin problem, but a different skin problem from NOMID, was referred
to Raphaela, and this patient had pustules all
over the body.
A nine-month-old child, with pustules all over
the body also had cystic lesions in the bone throughout the bone x-rays.
This patient also responded to IL-1 inhibition.
Turns out this patient has a mutation and others have mutations in IL-1 receptor antagonist
leading to identification of a new disease, DIRA, the
deficiency of the IL-1 receptor antagonist.
We live in really one of the most wonderful times that you can imagine, I think anyway,
for doing medical research, biomedical research, because
the fruits of the genome project are now there and
allow us to move forward in many different ways.
Some of the things going on, as Bob alluded to, the same pathways we worked on in patients
with rare diseases are important in gout, probably in
type 2 diabetes, maybe in atherosclerosis, as well.
We also are working on a disease called Behçet's disease, common in the Middle East and Far
East, in which people get ulcers in their mouth, inflammation
in eyes and genitals, but this is a mixed audience,
so I didn't show that picture, and also Still's disease, a common form, not totally common,
but at least more common than some of the other diseases
I told you about, a disorder in which children develop
arthritis, a rheumatoid arthritis like condition, with fevers.
There are other areas also of interest.
Rheumatoid arthritis, there are great advances being made through Peter Gregersen's consortium
looking at the genetics of rheumatoid arthritis.
We're beginning a collaboration with a group at Hopkins with regards to the genetics of
scleroderma.
And even man's best friend is benefiting from this.
This is the Shar Pei dog and Shar Pei dogs actually have -- it's been bred with the same
selection as their wrinkled skin.
They get a fever syndrome and the gene was recently identified for the fevers of Shar
Pei dogs.
So, in any event, this table we'll dispense with.
It's a cataloging of all these diseases; we call them
autoinflammatory diseases that involve these pathways.
In any case, the future is bright for NIAMS.
But in the last minute I will simply say that I think that perhaps the intramural program
of NIAMS could use a new name.
So the new name that I would like to propose is PICME.
PICME stands for patient centered.
Here is a picture of Raphaela and Nikki Plass with one of their patients.
Intellectual freedom.
A picture of our first scientific director, Henry Metzger, who told me here are some resources.
Go take them and have a good time.
Chutzpah.
You're wondering who will be shown with this picture.
It's the good Dr. O'Shea who is the originator of the especially virulent Irish chutzpah.
Mentoring is very important to us in NIAMS, and here is a photo of Paul Plotz, certainly
one of our most respected mentors in the Institute, but many
others could also deserve being featured there.
Then finally, ecumenical.
There we have our leader Steve Katz, NIAMS director, but really someone who has taken
a global role in terms of world health, in terms of national
issues, really approaching patients and researchers and
pharmaceutical firms across the spectrum.
So he is especially deserving of recognition here.
And, even though I have moved to another institute, you see they have us in other institutes dress
up in costumes and perform, we were thinking we
weren't singing at this time but we were thinking happy
25th anniversary to NIAMS, or PICME, will always be NIAMS at heart.