>> James: Scientist, today he'll talk about
developing implants for biosensors
that can match an individual's metabolism with drug dose.
>> Thank you, James for the kind introduction.
Let's see if I can share my slides here.
All right, here we go.
Good morning to everyone.
My research program is really building upon this idea
of having humans at the center of physician medicine.
And we're inspired by the realization that human biology
is very beautiful, but also very diverse.
So in this very limited sample of all humankind,
we can appreciate that there are different
ethnic backgrounds, different skin colors,
different eye colors and different sexes,
and yet our approach to drug therapy for many decades,
in case all of these beautiful diversity into a single model
of drug metabolism,
in which we assume that if you were to take a medication,
for example, in the form of a pill,
and we had a means of looking at the concentration
of drug mitigation in your bloodstream,
we would see the levels rise and fall following a specific
drug elimination profile with a hope that we could take
something like the maximum peak concentration
of these medication in your blood,
and use that to develop a functional therapy,
to treat any disease.
Now, all of you are familiar with this concept of, well,
I have to take my pill every eight hours or every 12 hours.
And the idea behind those, these strict time events
is that we can slowly build the concentration
of your medication and following these black trace
on the right hand side of this slide
to hopefully reach a steady state
where we called it within a therapeutic window.
However, you can imagine that because
we have all of these beautiful diversity in humankind,
it is very easily to miss that therapeutic window
to then reach either excessively adverse effects
or maybe ineffectively low levels of the drug.
This is not a big problem for something like aspirin.
You will need to take a lot asprin to reach toxic doses,
but it can be a problem for drugs that are
by themselves toxic to the human body.
So this is just one example of a very old anti-seizure drug
called phenytoin.
And I'm just gonna bring your attention to these graph
on the right hand side of this slide,
each one of these red dots represents the big plasma
concentration or the big concentration in blood
of different patients that took a given daily dose.
And if I can focus your attention on a dose of five
milligrams per kilogram,
you can see that for these large group of people,
I'm sorry, for these large group of people,
there's a deviation in the plasma concentration on the drug
that we reached of about another mile to go sometimes more.
So really the diversity severely affects drug metabolism.
And unfortunately,
the only approach that we currently have to addressing
these subject viability is to use an array of doses
that we have to experimentally give to the patients
so that we can hopefully find a dose
that gives the most benefits
with the lowest amount of side effects.
We think we can do better.
We think we can develop technology
that can address this issue at the point of care,
in a simplified format.
Another limitation of our many decades,
long approach to drug metabolism,
drug therapy is that we assume the metabolism is a constant,
however, we all are active.
So you have to think about the fact
that you're taking this medication every eight or 12 hours,
but maybe you run a marathon.
Maybe you drank more water or less water,
or maybe you had a very fatty burger.
And all of those elements of your daily routine
will be changing the way in which...
The speed and the way in which
you're metabolizing these drugs.
So the vision for my lab is that the development of sensing
technologies supporting the continuous real time measurement
of specific molecules directly within the human body
of a specific therapeutics within the human body
could potentially transform the way in which we study
and understand human health,
but also the way in which we study,
understand, diagnose and treat human diseases.
We think that such as technology, could for example,
enabled the measurement of the highly precise measurement
of patient specific drug metabolism,
so that we could potentially move one step forward
towards this idea of precision medicine,
in which we are determining the dosage given to a patient
based on actually measured data
as oppose of a populational average
or through the estimate of the one capsule by mouth,
three times a day.
We also think that these technologies could enable important
medical applications, like for example,
feedback-controlled drug delivery,
in which we are now coupling a little sensor that monitors
the levels of the drug in your body,
which is connected to a drug delivery device, a drug pump,
via computer algorithm.
So we can finally tune the concentration of the drug
in your body to keep it within therapeutic levels,
potentially avoiding toxic peaks
and ineffective low concentrations.
And then finally,
if we allow ourselves to dream about the future,
we can imagine incorporating these technologies
into our current infrastructure of portable wearable devices
so that we could potentially achieve
the real time assessment of health status.
By for example, tracking in real time,
the concentrations of drugs, metabolites, and biomarkers,
as we are undergoing our daily routines.
Now the approach that we have decided to pursue as a group
to kind of bring these concepts to our reality,
focuses on the development of this technology
that I'm showing you on this slide.
This technology is called electrochemical,
aptamer-based sensors.
The initial development of this platform was performed by
Kevin Plaxco and colleagues
at the university of California, Santa Barbara,
about 15 years ago.
And what my laboratory is doing
is we're really trying to push this to work
directly within the human body.
So we can do real time measurements of drug metabolism
in specific individuals.
Now, just to give you a quick description of the technology,
we have an electronic conductor.
And in this cartoon it's represented as a gold wire
this yellow thing.
We use chemistries to make that conductor compatible
with the human body.
So we will minimize nonspecific binding of proteins
and foreign body attacks,
trying to eliminate this from the system.
We call these chemistries monolayers,
but there are just different types of chemistries
that we use to protect the conductor.
We also functionalize these metallic conductor,
with a synthetic piece of DNA that we select in vitro
because it binds very strongly to specific molecular target,
for example, a drug.
And finally, we modify that synthetic piece of DNA
with a molecule that we call a reporter,
and it is simply we can give electrons to,
or pull electrons from, and very importantly,
when we immerse this interface in a sample of blood
and in the presence of the molecular target
that we're trying to send the receptor
and the target interact with each other.
And very importantly,
the target will cause a change in the physical confirmation
of that receptor, that in turn changes
the electronic properties of these reporter
that we have at the end.
We can interrogate these sensors serially
using different types of voltage perturbations.
This is just an example of candid picture.
We are sweeping the voltage of electrons.
We are recording the current output
from that voltage switch.
And what you see is that in the absence of target,
we have something that looks like a peak shade response
in black.
And then if we increase the concentration of target,
the expectation is that that signal will increase
proportionally the concentration.
And in fact, we can do this
for a series of different sensors
represented here and with different products,
for an antibiotic, for example, tobramycin.
And you can see that the signal of the sensor
can be directly correlated to the concentration of the drug
following these sigmoidal curve.
Now we can make these sensors small enough to feed it inside
of the veins of research animals.
This is just a photograph of one of the devices
that we have fabricated to date.
This is a bundle of wires with a sensor of the deep end,
the total diameter of this device, about 200 microns.
So roughly the size of a human hair.
Because these sensors are very malleable and stuffed,
we have to engage them into medical grade calendars
to give structural support to them.
We then go ahead and perform surgery in research animals.
Specifically, we work with mice and rats.
We implant the sensors into their veins.
We also have drug infusion lines,
and we ensure that the sensors are placed in locations where
there's plenty of exchange of blood
so that we can quickly calibrate with any concentrations
of drugs available in the system.
And the result of is that for the first time we can achieve
real time, highly specific, ultra precise measurements
of drug metabolism in Vivo, in the veins of living,
breathing rats.
This is an example of a baseline signal
in response to an Ivy bolus injection of the antibiotic,
tobramycin and we do these twice.
And you can see the sensor responding to that
directly in the vein of an animal.
Of course, the idea here is
that the platform is generalizable
to addiction of other drugs,
so remember by simply switching the synthetic piece of DNA
that we use as the receptor for a piece of DNA that binds
to different molecules, we can then achieve real time,
continuous measurements of these other molecules in Vivo,
and in these now somewhat outdated panel of profiles,
I am showing you the different examples of drugs
that we have been trying to measure in Vivo.
Some of them done buy us, some others done by collaborators
from China and other parts of the world.
We have now successfully monitored concentrations
of antibiotics like animates and gentamycin,
tobramycin from the family of
the aminoglycoside antibiotics.
Also, glycopeptide vancomycin as well as chemotherapeutics
like doxorubicin, irinotecan,
and a very important biological molecule,
the energy molecule, adenosine triphosphate or ATP.
Now all of these drugs here
on the majority of the panels have a very narrow therapeutic
window that is controlling their levels in blood
is very important to prevent toxicity.
And so the obvious connection is, well,
can we now develop a computational system that will allow us
to connect these sensors to a drug delivery device
in the way we envisioned it earlier in this presentation?
And so this is the very early demonstration we have done,
we now can connect a drug delivery device
that will be infusing drug into the body.
We have this sensor place and connect it to our electronics.
We use a computer model with a PID controller.
And just to keep this very simple,
this is the same type of controller that all of you have
in your kitchen ovens to adjust the temperature
of the oven and keep it constant.
We're using the same technology here.
Now, since it's our monitoring concentrations of drug
in real time, we turned on the controller
and set a reference point to for example, 30 in this scale,
so now the drug will start infusing drug.
Our sensor will pick up the infused drug
and monitor in real time until it reaches a threshold
that we set before turning on the controller.
And now we can call that concentration constant
for as long as we want.
And when we turn off the controller,
we can see again how the drug gets metabolized by the body
of, in this case, our rat subjects.
So we think that there are many opportunities
for this technology in this space of diagnostics
and personalized drug therapy,
particularly in the context of chemotherapy.
And so with these,
I'm just gonna finish this by thanking my students,
we're a very young group of Hopkins.
This is my second year in this institution
and we're starting to receive support,
you know, institutional support from Hopkins
but also from private companies
as well as external foundations.
And we're really trying to push this forward to the clinic.
Thank you very much for your attention.
>> James: All right, great, thank you, Netz.
So Alison and Sarah ask,
which diseases or conditions do you think might be targeted
first for this technology?
>> Thank you, great question.
We have, we're currently focusing on infectious diseases
as well as treating cancer.
And I think the cancer example is the simplest one.
So I'm gonna explain it to you very quickly.
If you are undergoing chemotherapy,
usually the way you receive that medication is,
you're sitting in a chair, you have an IV line
that is constantly dosing the drug.
And what we do is we will draw blood out of the patient
after a certain time interval
to then quantify in a centralized facility
far, far away from the patient.
What the level of that drug is in your body.
But the idea here with this technology,
remember it's only 200 microns in diameter.
So the size of a human hair,
we can slip that line into the vein at the same time
that you're receiving your medication.
And then monitor in real time,
how your body is responding to that drug.
So hopefully we can achieve truly personalized,
but also highly precise drug therapy
under those circumstances.
>> James: Great, thank you.
Second last question is how much does your team collaborate
with, or is aware of similar efforts
going on in Themaker and do it yourself, bio communities,
people like Dana Lewis, or DIY pancreas system?
>> This is a great question.
We are collaborating with a lot of people.
I could mention a few,
a few instead of names of institutions,
but we are closely collaborating with UC San Diego
to develop these into wearable patches.
So we can do measurements, interstitial fluid.
We are actively collaborating with Makerspace
here in Baltimore called Open Works.
And just to illustrate the extent of collaborations
that we have.
I'm just gonna turn off my visual background very quickly
and show you that I just build my first 3D printer here
'cause I can't be in a lab, so I'm gonna be printing parts
for my students so they can continue
to develop the technology from far away.
So heavily involved with all the, do it yourself,
people in the community.
>> James: Great, alright, thank you very much.
>> Thank you.
>> Okay, so our speaker is...