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Hello. My name is Alan Remaley.
I am a senior investigator at
the National Heart, Lung, and Blood Institute,
which is part of the NIH,
where I am very fortunate to be able to do research
on how fats, like cholesterol and triglycerides,
cause heart disease.
But before I tell you about my research,
I'd like to make a few general comments about science
that I have learned over the years,
but have been true since the 1600s
when Francis Bacon first described the scientific method.
The first is, like most other human endeavors,
it's usually very useful to collaborate with other people,
particularly when trying to make progress in science.
So, along the way,
I'd like to point out a few key people in my own research.
Secondly, science can be very unpredictable,
which makes it both frustrating and exciting.
Research sometimes on obscure topics,
or in my case in a rare disease,
can sometimes uncover unexpected findings
that may have more broad application.
And then finally, as you will see,
it's always a good idea to understand
when your experiments don't work,
particularly when they provide information
that's contrary to what you think should happen,
because many times this offers the best opportunity
to learn something new.
Now, the inspiration for my research
came from a chance encounter with a patient.
She was a young woman,
had a disease called Familial Hypertriglyceridemia,
which just simply means her triglycerides
in her bloodstream were too high.
And triglycerides, like other fats,
don't dissolve well in water,
so they are transported in blood
in very small particles called chylomicrons.
And when they are present at very high levels,
they can clog small blood vessels and damage the pancreas,
and unfortunately, this happened to our patient.
And when she asked me what we could do to help her,
I didn't have a good answer
because there is not a specific treatment or cure
for this rare disease,
but it motivated us very much to work on this problem.
Next, we did something that we could have never have done
even just a few years ago.
With the help of Dr. Rich Pastor,
who is a friend and another senior scientist
here at the NIH,
we used a very powerful supercomputer called Anton 2
to try to understand how the protein
that's defective in our patient,
called apoC-II, serves to act as a stimulator of LPL,
which is the plasma enzyme
that degrades triglycerides in the bloodstream.
Using this information, Dr. Anna Wolska,
a very talented research fellow in my laboratory,
she first designed and then synthesized a very small piece
or fragment,
which we call a peptide of the larger apoC-II protein.
And she showed that this small peptide
was actually more potent
than the full-length protein in activating LPL.
And then we were very thrilled
when we made a genetic mouse model of the defect
that our patient had
and found that our peptide actually blocked
the accumulation of triglycerides in the mice.
But as I said earlier, science can be very unpredictable.
It was at this point in our research
where we had a very perplexing finding.
When we tested the peptide
in other mouse models of high triglycerides,
it always worked whether apoC-II was present or not,
which indicated it may be working by another mechanism.
And a clue to understanding this puzzle
is that many important metabolic steps
are regulated not only by activators,
but also by inhibitors.
Dr. Dennis Sviridov, a very talented biochemist in my group,
then was able to demonstrate
that the peptide blocked the inhibitor of LPL,
which is called apoC-III.
And this was an unexpected and very fortuitous finding,
because in late-stage clinical trials,
other drugs that block the inhibitor of LPL
seem to protect against heart disease by lowering cholesterol.
So, even though we did not intend to do so,
we developed a peptide that had a dual mechanism of action
in lowering both triglycerides and cholesterol.
So, the peptide was recently licensed
to a major pharmaceutical company,
and I'm very optimistic; one day,
with probably a lot more hard work
and maybe a little bit of serendipity,
that we will have a new treatment for our patient
with high triglycerides that may also turn out to be useful
for the many patients with heart disease
that have too high cholesterol.
So, I'd like to finally finish with a quote from Francis Bacon,
the founder of the scientific method.
He once said that "Science is but an image of the truth."
I'm not sure we are clearly seeing the whole picture
or the whole truth,
but I do think that our research has revealed a glimpse
of lipoprotein metabolism
that we will be able to build upon in the future
to better see and understand how we can help our patients
with lipoprotein and lipid disorders.
And that is how science is supposed to work.
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