[train whistle]
[applause and cheering]
[instrumental Ramblin’ Wreck from Georgia
Tech fight song]
Steve McLaughlin: You’re listening to “The
Uncommon Engineer.”
I’m your host, Steve McLaughlin, dean of
the college.
Announcer: We’re just absolutely pleased
as punch to have you with us.
Please say a few words.
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Steve McLaughlin: Hi everyone, and welcome
to “The Uncommon Engineer” podcast.
I’m Steve McLaughlin, Dean of the Georgia
Tech College of Engineering.
Our podcast is all about how Georgia Tech
Engineers make a difference in our world and
in our daily lives.
In this episode, we’ll be talking about
gene therapy.
It’s an experimental technique that uses
a person’s genes to treat or prevent a disease.
While it’s still in its formative stages,
in the future gene therapies might take the
place of invasive surgeries or drugs.
Our guest today is Dr. James Dahlman.
He’s a professor in the School of Biomedical
Engineering at Georgia Tech and Emory.
James’ work is at the intersection of nanotechnology
and genetics, specifically gene therapy.
Welcome to the program, James.
James Dahlman: Thank you very much for having
me.
Pleasure to be here.
Steve McLaughlin: So, you know, we’re hearing
lots in the news about so called immunotherapies
where novel techniques of using your own immune
system to attack disease, CAR-T, and maybe
even CRISPR.
Can you say a little bit about that and why
this is such an exciting area?
James Dahlman: Yes.
So I can say as somebody who works in gene
therapies, it’s a very exciting time to
be in this field right now.
The potential for gene therapies is tremendous
because they treat disease by going after
the root source which is the genetics itself.
I think that gene therapies can be sub-divided
in to three buckets: In one bucket the goal
is to produce a lot of the gene; in this case
the disease would be caused by not making
enough.
The second bucket is designed to turn off
genes; in this case the disease would be caused
by producing too much.
And then the third bucket, you’re actually
going in and editing the genome itself; this
is the newest form of genetic therapy but
it still has some promise.
There are many other examples.
Some of the work that we perform in my laboratory
is designed, again, to solve a very simple
problem.
If you want a genetic therapy to work, you
need to get it to the right cell type.
If you have cystic fibrosis and you want to
change gene expression in the lung in order
to treat the disease, you want that drug to
go to the lung.
You don’t want it to go everywhere else.
Once again, the simple problem of getting
the drug to the right place at its core is
an engineering problem.
Steve McLaughlin: One of the things you talked
about was turning off or silencing a gene.
Before you talk about the specific therapies,
can you give us a little bit of primer on
what that really means?
James Dahlman: The easiest way to explain
this is to go back to sort of biology 101,
and that is DNA makes RNA which makes protein.
So the DNA is like the blueprints—it’s
what makes you, you.
And the DNA’s job, or one of its jobs, is
to produce protein which really does the work.
So DNA will encode for a certain protein.
If the DNA gets a mutation in it, it will
encode for the wrong protein and that protein
can cause disease.
In the case of shutting off a gene, what we’re
really doing is shutting off the protein production.
And we can do this at two different levels:
The first level is shutting off the RNA production,
and the second level is by changing the DNA
itself.
The most advanced clinical trial so far work
at the RNA level; they aren’t quite there
yet with the DNA stuff.
Steve McLaughlin: Can you say a little bit
about your own work and the kinds of things
that are going on in your lab regarding silencing
or turning off genes and what’s the application?
James Dahlman: It’s a really exciting time
to be a scientist in gene therapy right now.
My lab focuses on one simple problem: How
do we get the drug to go to the right place?
This problem lies at the interface of chemistry,
of what we call nanotechnology, and biology
because we are packaging drugs inside nanoparticles,
which are just very small particles, in order
to get them to go to the right tissue, and
to protect them from being degraded and attacked
by your body.
So my lab focuses on developing nanoparticles
that target genetic drugs to the right tissue.
A nanoparticle is simply a small particle.
I’m about 6 feet tall, and I am 1.8 billion
nanometers tall.
The systems that we create are about 50 nanometers
in diameter.
They’re little spheres.
We package the genetic drugs, whether it’s
DNA, or RNA, inside these little spheres,
and the nanoparticles act as, almost, mail
carriers that take them to the right cell
type—the disease cell type—and help them
avoid healthy tissues.
This reduces side effects and it improves
drug efficacy.
Steve McLaughlin: So I’m kind of imagining
these nanoparticles, you know, with the therapies
or drugs inside of them, and somehow they
get in to your body, and they’re going throughout
the body.
How do they know where the right place to
go is, and then once they find the right place
to go, how do they then deliver the therapies
to the tissue or the cells?
James Dahlman: It’s another great question
and, again, it lies right at the interface
of chemistry and biology and engineering.
When you take an aspirin, the aspirin doesn’t
have flippers or heat seeking technology that
goes right to your headache; it kind of goes
everywhere.
When you take a genetic drug, if you didn’t
target it in any way it would do the same
thing.
So the way I would think about this is you
can divide the process in to two steps: The
first step is getting to the right tissue.
So just imagine that you’re a nanoparticle,
you know, you’re minding your own business
but suddenly you get injected into this blood
stream.
The blood stream is chock full of proteins
and lipids and all sorts of stuff here.
Your blood isn’t just water; it’s like
a soup that’s full of all these biomolecules.
So you may interact with some of the biomolecules,
but you’re passing by the heart, you’re
passing by the lung, you’re passing by the
pancreas, the liver—all these organs.
And every organ is going to look a little
different to you.
If we designed the nanoparticle the right
way—let’s say for cystic fibrosis where
you want to target the lung—we designed
it in a way that the lung looks better to
you than the liver, or the lung looks better
to you than the kidney.
And so you end up in the lung more so.
That’s the first step: getting to the first
place.
Once you get there, there’s a second, very
exciting and interesting step, which is getting
into the cell itself.
So although the biology and the biological
processes that govern this are still somewhat
unclear, we do know a few things which is
that cells gobble things up actively.
Just like us, cells need nutrients, and they
get nutrients from their environment, from
their neighborhood, if you will, and from
the bloodstream.
So cells gobble stuff up very actively.
Ideally, your nanoparticle is designed in
such a way with such a chemistry that makes
it tasty to cells so they end up gobbling
it up.
This allows the drug to get into the cell
where it can do its job.
So again, I would sort of divide it in to
two parts: First, getting to the right tissue
and then, second, getting into the cell once
it’s at the tissue.
Steve McLaughlin: So the delivery of the nanoparticles
to the cells, that really sounds like an engineering
problem.
Can you say more about the drug delivery,
because it’s so specifically targeted, what
your students are doing with that?
James Dahlman: My students are developing
what we call “DNA barcoding technologies.”
And the easy way to think about this is we’ve
developed technologies that allow us to perform
a few thousand experiments all at once.
The technology behind it is pretty fun.
Think about it this way: We can make a giant
library of nanoparticles.
nanoparticle 1 might be small.
nanoparticle 2 might be large.
Nanoparticle 3 might have a positive charge
on it.
Nanoparticle 4 might have a negative charge
on it.
We can make thousands of different nanoparticles
with different chemical structures.
We don’t know which ones are going to work.
So how can we test thousands?
Well, the way we do it is we use DNA as a
molecular tag.
So nanoparticle 1 gets DNA barcode 1.
All that means is nanoparticle 1 carries—instead
of carrying a drug to turn off a gene, it
just carries a little tag that’s a DNA sequence
that we know.
Nanoparticle 2 carries a different DNA tag:
just a different sequence, again, that we
know.
And you can do this you know many times in
a day.
My students have made up to 250 Nanoparticles
each with its own molecular tag within a day.
You can then mix all the particles together
and administer them in a single experiment.
You then isolate the DNA, and you can use
deep sequencing—again, this technique that
you spit in a tube and send it to Ancestry.com
or to 23andMe.
We use that same machine that—the DNA sequencing
machine—to analyze how all of those DNA
sequences behaved at once.
So if you do 250 different nanoparticles and
250 sequences, and you run your experiment
and you take out the cells, and it turns out
that barcode number 17 shows up in those cells
more so than the other barcodes, that means
that nanoparticle number 17 might do a good
job.
So this allows us to perform hundreds and
thousands of experiments simultaneously.
And actually using this process, we’ve been
able to identify nanoparticles that do target
new tissues and new cell types.
So it’s pretty efficient.
I think we can accelerate the development
of drugs this way.
Steve McLaughlin: So let me get this right.
This is incredible.
So I think the way that people have done experiments
for hundreds of years is they try one thing
at a time; they try one therapy at a time
and you then test that therapy.
You’re saying, now you can do that same
thing: Instead of testing one therapy at a
time, you can test hundreds or thousands of
therapies at a time.
And I guess your goal is, in this case, it’s
about the delivery of the nanoparticle into
the cell, and all then you need to do, is
read out and then examine the cell and see
which of the nanoparticles got through.
Do I have that right?
James Dahlman: Yes, that is exactly right.
And I can tell you that it is a very exciting
time to be in the lab right now because I
thought up this technology a few years ago.
It took a while to engineer it so that it
was robust, but it is now working.
And in a typical experiment now, one of my
students will test about 250 nanoparticles,
and we’ll analyze the delivery to, let’s
say, 30 cell types.
So 250 times 30 is what—whatever that is—7500
experiments performed at once.
The data sets that we’re generating now
are so big and so much bigger than anything
I’ve reported in my career, that we actually
had to develop a bioinformatics pipeline to
analyze the data sets because there was no
pipeline to my field to analyze it.
It’s pretty fun because what you can find
is that let’s say nanoparticle 17 does well
in lung cells, but really doesn’t do well
in heart cells.
Well, that’s great because you can have
specific delivery to the lung, and so we can
measure delivery to our target tissues as
well as all of our, what we call “side effect
tissues” or “off-target tissues,” in
a single experiment.
So we can do years of work basically in three
days.
And I think this is a real step-function change
in the ability to do these experiments.
We are interested in commercializing this
in order to get products to patients more
quickly.
The ultimate goal is to accelerate the development
of genetic therapies, and I think this platform
really does stand a chance to do that.
We know that we’ve received a lot of interest
from the field so far from companies that
are already in the clinic, in fact, and they
view this technology as very promising, and
a way to accelerate how quickly genetic therapies
actually make it into clinical trials and
actually make it into patients.
So we’re really excited about all of these
opportunities.
Steve McLaughlin: So the idea of barcoding,
you know, nanoparticles to get to tissues
for addressing diseases is absolutely fascinating.
How close is this to actually being used,
say, in humans or how applicable is it to
humans?
And looking in your crystal ball, when do
you see those kinds of things having an effect
on patients?
James Dahlman: So I do think our work has
implications for human disease.
I’ll give you an example that’s pretty
exciting right now: We have initiated a collaboration
at the National Cancer Institute outside D.C.,
and this collaboration is with a surgeon.
This surgeon does this very cool thing: He
operates on patients that have liver cancer.
He would do it anyway; it’s part of the
normal procedure.
And after he does the surgery to remove the
tumor, he actually made a machine that keeps
the tumors alive for about a week.
And, as you can imagine, these things are
very rare samples and they needed to be treated
with respect.
So one of the advantages of our system is
we can essentially perform a few hundred experiments
using one patient tumor instead of performing
one experiment with a patient tumor.
And although we haven’t started these experiments
with him yet, I am hopeful that we’ll be
able to start experiments like this where
we’re screening directly in patient samples
maybe within the next two years.
That would be great.
I think the key point here is that when you’re
dealing with patient samples, and so I think
it actually is an advantage of our system
that we can test hundreds of things per sample
instead of one thing per sample.
Steve McLaughlin: So you talked about the
three different approaches to gene therapy,
one of which was gene editing.
I’ve heard about this technology called
CRISPR—about what CRISPR is and the kind
of work that’s going on in your lab?
James Dahlman: CRISPR is, arguably, the most
exciting biotechnology discovery certainly
of the 21st century, so far.
Put succinctly, CRISPR allows us to edit the
genome very easily.
Even five years ago, if you wanted to take
DNA and change the DNA sequence, you could
do it using things called zinc fingers and
talons, but it was going to take a lot of
money, and it was going to take a lot of time.
CRISPR does the same thing as zinc fingers
and talons—it edits DNA, it changes DNA
sequences, but it’s really, really easy
to use.
And so now, for the very first time, scientists
can do something as simple as edit 10 different
genes, 100 different genes, and see which
gene causes a tumor to grow.
You can accelerate these scientific studies.
Therapeutically, CRISPR can be used to edit
cells so that they target tumors more effectively.
And in the future, CRISPR may be used to edit
the genome inside human patients as well in
order to turn off a gene that’s causing
disease.
So from our lab’s perspective, we do a lot
of work on CRISPR.
CRISPR’s not going to work unless you get
it into the right cell, and so from our perspective,
we’re just trying to get it into that right
cell.
I will say, from a scientific perspective,
CRISPR is one of the most, if not the most,
exciting technological development I have
ever been exposed to.
It is changing how things are done.
Steve McLaughlin: I’d like to change directions
just a little bit and hear you talk about
your own path, maybe even from junior high
or before, how you made your way to Georgia
Tech and how you made your way to wanting
to study this area and become a biomedical
engineer.
James Dahlman: When I went to MIT and Harvard
Medical School for my graduate work, I was
in what’s called the HSC program.
I started drifting more towards biology and
medicine.
So at MIT, I did my Ph.D. work in materials
science, but you’re also forced to take
two years of medical school at Harvard with
the medical school students.
And so I remember one very interesting day
as a first-year graduate student walking out
of a pathology exam at the medical school
and then walking right in to a quantum mechanics
exam after taking the bus—so it really does
stretch your brain a little bit.
As I got in to the medical school classes,
it became clear that biology was just so elegant
and it really is a beautiful science.
It also became clear that engineering was
going to play a huge role in the future of
biology, and that’s definitely been the
case.
I came to this point by just following my
natural love for science.
I’ve never done science that’s boring
to me, and I only do science I find interesting,
and this has been a huge advantage.
Steve McLaughlin: Professor Dahlman, I have
one last question for you: What makes you
an Uncommon Engineer?
James Dahlman: I think the thing that is most
uncommon about me as an engineer is the fact
that I’m willing to, and excited by, the
idea of merging completely different fields
together.
My lab right now is at the interface of genomics,
chemical engineering, and nanotechnology.
And as far as I know, we’re the only lab
that’s sitting here.
I think it’s a lot of fun to really be out
there on the cutting edge trying to marry
new fields together.
I think that’s what really sets us apart.
Steve McLaughlin: Fantastic!
Thanks very much, James.
We really, really appreciate you being here.
James Dahlman: Thank you very much for having
me.
It was a real pleasure.
Steve McLaughlin: Be sure to tune in next
month when we talk to Professor Brendan Saltaformaggio
about cybersecurity.
[crowd noise]
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Tech fight song]
