My work is gravitated towards management of type one diabetes,
it's what I'll talk about.
This is very complicated disease for patients to manage,
and so our job is to make this a disease they can live with.
And we have many patients now that have lived for 50 or
60 years, but it's a lot of work.
And so, there is clearly a need for a cure for this disease.
And, so I'm gonna come over here so
I can see which slides are coming up.
So this is a disorder now that is also increasing,
as is type two, not quite at the same rate.
And it's only about 4 to 5% of patients
with diabetes have the type one kind.
And type one diabetes is a disorder predominately of
childhood.
About 45% of people who end up getting type
one diabetes get it before the age of 10.
It is an autoimmune disease.
Where by the immune system which is suppose to protect us
against foreign things like bacteria and viruses.
The immune system turns on itself and attacks, and
destroys the cells in the pancreas that make insulin.
They're called the beta cells.
There's a lot of other auto immune diseases you've probably
heard of like rheumatoid arthritis, and lupus, and
those kinds of disorders.
And because it knocks out the pancreas' insulin production.
Patients need to take insulin for life, to stay alive.
And before 1922, when insulin was discovered,
people uniformly died of this condition.
So insulin is something you've heard about from
other speakers today.
It's a hormone, and
a hormone is something that is made in one place and
has actions elsewhere.
So, insulin is made in the pancreas and
goes in the blood stream, and it goes to tissues,
especially muscle and fat tissues.
And it allows sugar to enter into the cell where it is burned
as energy.
And the sugar that I am gonna be talking about is predominately
glucose, a term you may already be familiar with.
So diabetes can be a really bad disease.
It damages the little blood vessels in the eyes,
the kidneys and the nerves.
It damages those organs, it also effects large blood
vessels leading to the brain and to the heart.
And so, it can contribute to heart attacks and
strokes as well.
And so, diabetes now, type two and type one.
Because they both are diseases of high blood sugar.
Are the leading cause of adult blindness in the United States.
Leading cause of end stage kidney disease.
The leading cause of non-traumatic amputations in
the United States.
Now if you have diabetes, you have a two to four fold increase
risk of having a heart attack or stroke.
So our job is try to keep the glucose levels
as close to normal as possible to prevent complications.
Because it's been shown that tight blood sugar control will
prevent complications.
And so this is a challenge.
So we have to teach patients how to replace insulin the way that
the body does, and that's a challenge.
We don't respect what our body does for
us until that organ breaks down, and it stops doing what it does.
So we have to teach patients how to dose their
insulin, based on the foods that they eat.
We have to teach them how to give insulin injections or
use an insulin pump.
And we have them test their glucose levels by a finger
stick--blood sugar level.
Before meals, at bedtime, anytime they feel high or low,
before exercise, before driving.
So they do a lot of blood sugar testing during the day as well.
And they can also
adjust their insulin dose based on their blood sugar level, so
they can bring it down with extra insulin.
So, this is a challenge,
because we teach patients how to adjust their insulin based
on the carbohydrate content of the food.
And if you looked at your sandwich, patient with type one
diabetes has to figure out how many carbs are in that wrap.
How much sugar is in the sauces that it's in that.
They could look at a bag because the carbohydrates
are labeled in the bag.
But think about eating a slice of pizza how thick is the crust,
how much sugar is in the pizza sauce.
How much sugar is in the cheese, etc., it's a challenge.
We ask patients because insulin's
these days don't work immediately.
We ask them
to dose the insulin 15 to 20 minutes before the meal.
Because that's how long it takes the insulin to get
into the bloodstream.
And if you think about having lunch on the run,
it's hard to wait 15 or 20 minutes.
So that's a challenge.
They have to incorporate, well, have I been physically active?
Because then I have to take less insulin.
Am I stressed?
Have I been really inactive?
Cuz then I probably need more insulin.
And based on where they inject, how deep they inject,
how much skin is there.
Whether they have any scar tissue in that area,
it affects insulin absorption.
So this is a real challenge for
patients to have to overcome all these different features.
And so, the other drawback is that the drug that we're using,
insulin, to bring glucose levels into the normal range.
Can also cause a low blood sugar reaction.
So the narrow range is very tight, and
you go a little below the normal range and
you can have significant symptoms from a low blood sugar.
And serious low blood sugars are called sever hypoglycemia.
Is defined as needing insulin, or needing help from somebody
else to treat a low blood sugar reaction.
It occurs in about a quarter of patients per year.
The symptoms can take up to hours before they fully resolve.
It can cause seizures.
And we think that 4-6% percent of patients with type one
diabetes will ultimately die of a low blood sugar reaction.
So our treatment is effective but
it also potentially can lead to severe outcomes.
So if you think about all the things I talked about.
Patients with type one diabetes really think about their
diabetes all the time because everything they do during
the day affects their diabetes.
So this is doing a finger stick,
they do this four to six times a day on average.
These are injections that they have to give themselves
with needles and pens, syringes.
Patients can now wear insulin pumps that delivers
the insulin throughout the day.
And they can tell the pump how much insulin they wanna have
delivered.
But this is what most patient’s feels, they feel
they are diabetic they’re different from everybody else.
They have to give themselves injections all day and so
they really feel like pin cushions a lot of times.
And so what we do research wise gives them hope because what
they really want is a cure for this disease.
So that's why a lot of people are working very
hard to find a cure.
So I'm involved in a number of things that are ultimately,
hopefully will lead to a cure.
And the one thing I want to
talk about because Immunology Lab I've been working with
is doing some exciting things is immunotherapy.
So, this is an auto-immune disorder, so
the immune system goes awry.
So, if we can in some way block the immune system from attacking
and destroying those cells.
Patients may not develop type one diabetes, and
then don't need to treat themselves with insulin.
So, this can be done in two ways.
And we'll talk a little bit more about this, but
we can either block the cells that are doing the attacking.
Or there are also some protective cells called
regulatory cells that I'm going to talk more about.
If we can support them, then we might be able to also
prevent the disease from occurring.
So this is a diagram of those two cell types.
And so these T effector cells are the ones, ordinarily,
their job is to attack foreign things such as viruses and
bacteria and rid them out of the body.
And they also scan cells that have changed within the body
like early tumor cells, cancer cells.
And they attack and destroy those as well.
But they're clearly not meant to attack self tissues,
otherwise we wouldn't be alive.
And so, these regulatory cells here prevent the immune system
from attacking and destroying self tissues.
So what happens in type one diabetes is,
these cells fail both in number and in function to
block the T effector, the bad attacking cells.
For some reason there is a trigger that causes the immune
system to attack and destroy insulin producing beta cells.
And so a number of studies, some of which I've been involved
with have been geared towards preventing
those attacking cells from doing the attacking of beta cells.
And so mostly what we've done, in patients who have new onset,
type one diabetes.
They saw about 20% of their insulin producing cells, and
if you can get them rapidly treated.
And get them regulated in terms of how much sugar and
starch they're eating in their diet, a lot of times they can
actually be protected from needing insulin.
So if you can preserve those last 20%,
you've done them a huge service.
And even if they need a little bit of insulin,
it remains remarkably easy to control.
If the pancreas is still able to kick in and produce some insulin
during the day to help smooth out glucose levels.
So these are a number of drugs that have been used.
I was involved in the design and study of an antibody
that targeted those cells that were doing the attacking.
And invariably, when we do a lot of studies on rodent animals,
things work beautifully.
And so, when a lot of these drugs were used in mouse models
called the NOD or non obese diabetic mouse,
they develop type 1 diabetes.
They worked very effectively but
we found is the human immune system is much more complicated.
And often times these types of therapies aren't as effective in
humans.
And at higher dosages that lead to good protection against
the progression of type one diabetes and
there tends to be side effects from these medications.
Such as fever, headache, a drop in blood pressure, rashes.
And you can get reactivation of viruses like Epstein-Barr rash
that causes mononucleosis.
And the problem with,
we don't know also the long term immunosuppressive effects.
So, actually we do know from experience and
using immunosuppressive drugs for transplant patients.
That they are increase risk for infections and ultimately for
cancers as well.
So we have a disease that we can mange with insulin so
we have to first do no harm.
And so these kinds of long term risks are a problem because we
don't want our patients getting infections,
we also don't want them getting cancers.
So, our lab, in combination with Dr.
Abdel Hamad, one of our immunologists have been looking
at the regulatory cells as supporting the regulatory cells.
Cuz if you can keep them functioning and
do their job of preventing the effector T cells,
the bad attacking cells, from turning on and attacking cells,
then that's an avenue of treatment potentially.
So these regulatory cells have been studied, and
it finds that their number and their function drops off
in people when they develop type 1 diabetes.
And we have been one of the labs that have concluded that
these cells die by something called the Fas ligand pathway.
Fas and Fas ligand are on the surface of the immune cell and
when two cells together posses these,
it causes the cells to die.
And why would they have this well think
about the immune system when it fights a virus or bacteria.
The immune systems revs up to fight and attack it and
you need something that kills those cells, and
brings it back to more normal numbers.
And so that's the Fas Fas ligand that's a good way it works.
But in that is activated in persons with new onset type one
in the regulatory cells it's activated.
And so the cell numbers drop off and their function drops off.
So we have found a way to block this.
So an antibody has been created that targets this phos ligand.
So if you target that so an antibody binds to the Fas
ligand, this is a surface protein on the immune cells.
And by attaching to it, it prevents from binding
with Fas and prevents those cells from dying off.
And the dosages that have been used,
at very low dosage you're not suppressing the normal
regulatory function of the immune system to
down regulate that in times of infection.
And when this Fas ligand is given to the NOD mouse,
it prevents it from developing type 1 diabetes.
That's exciting because what we're doing here is not
causing immunosuppression.
We're supporting the regulatory cells in the body that
prevent autoimmunity from happening.
So what we're currently doing is we're making a,
it's called a humanized antibody.
So if we can make antibodies in animals very well, but
if you If you make an animal antibody then that's a foreign
substance to a human,
and the human automatically attacks and destroys that.
So we're making a humanized antibody that attaches on to
this Fas ligand surface protein.
And we are then going to be testing them in human cells to
see their effects on normal human cells.
And seeing how immunity changes in persons without diabetes.
And then our ultimate goal is to test these in patients with
early onset type 1 diabetes.
And see if we can arrest the destruction of the insulin
producing beta cells.
So now we'd be only targeting a very small portion of
the population, those people who have nuance at type one.
Well, how would we know whether or
not somebody's going to develop type one.
And could we use this even before they've lost their 80% of
insulin producing cells.
So there are ways through screening of people who have
relatives with type one diabetes.
That we can see if they have positive antibodies, or antibody
markers in auto-immune diseases that we can test in the blood.
And if they're present, especially in increased numbers,
we know what,
we can predict what rate they'll develop type one diabetes.
And those who are at high risk for
developing type one diabetes in the next five years,
that's a natural target for giving this antibody to.
As long as it's shown to be safe and effective.
So that's my part.
Thank you.