Producing a gaseous messenger molecule inside the body, on demand
Method could shed light on nitric oxide's role in the neural,
circulatory, and immune systems

Date:
June 29, 2020
Source:
Massachusetts Institute of Technology
Summary:
Method could shed light on nitric oxide's role in the neural,
circulatory, and immune systems.



FULL STORY ========================================================================== Nitric oxide is an important signaling molecule in the body, with a
role in building nervous system connections that contribute to learning
and memory. It also functions as a messenger in the cardiovascular and
immune systems.


==========================================================================
But it has been difficult for researchers to study exactly what its
role is in these systems and how it functions. Because it is a gas,
there has been no practical way to direct it to specific individual
cells in order to observe its effects. Now, a team of scientists and
engineers at MIT and elsewhere has found a way of generating the gas at precisely targeted locations inside the body, potentially opening new
lines of research on this essential molecule's effects.

The findings are reported in the journal Nature Nanotechnology, in a
paper by MIT professors Polina Anikeeva, Karthish Manthiram, and Yoel
Fink; graduate student Jimin Park; postdoc Kyoungsuk Jin; and 10 others
at MIT and in Taiwan, Japan, and Israel.

"It's a very important compound," Anikeeva says. But figuring out the relationships between the delivery of nitric oxide to particular cells and synapses, and the resulting higher-level effects on the learning process
has been difficult. So far, most studies have resorted to looking at
systemic effects, by knocking out genes responsible for the production
of enzymes the body uses to produce nitric oxide where it's needed as
a messenger.

But that approach, she says, is "very brute force. This is a hammer to
the system because you're knocking it out not just from one specific
region, let's say in the brain, but you essentially knock it out from
the entire organism, and this can have other side effects." Others have
tried introducing compounds into the body that release nitric oxide as
they decompose, which can produce somewhat more localized effects, but
these still spread out, and it is a very slow and uncontrolled process.



==========================================================================
The team's solution uses an electric voltage to drive the reaction that produces nitric oxide. This is similar to what is happening on a much
larger scale with some industrial electrochemical production processes,
which are relatively modular and controllable, enabling local and
on-demand chemical synthesis. "We've taken that concept and said, you
know what? You can be so local and so modular with an electrochemical
process that you can even do this at the level of the cell," Manthiram
says. "And I think what's even more exciting about this is that if
you use electric potential, you have the ability to start production
and stop production in a heartbeat." The team's key achievement was
finding a way for this kind of electrochemically controlled reaction to
be operated efficiently and selectively at the nanoscale. That required
finding a suitable catalyst material that could generate nitric oxide
from a benign precursor material. They found that nitrite offered a
promising precursor for electrochemical nitric oxide generation.

"We came up with the idea of making a tailored nanoparticle to catalyze
the reaction," Jin says. They found that the enzymes that catalyze
nitric oxide generation in nature contain iron-sulfur centers. Drawing inspiration from these enzymes, they devised a catalyst that consisted of nanoparticles of iron sulfide, which activates the nitric oxide-producing reaction in the presence of an electric field and nitrite. By further
doping these nanoparticles with platinum, the team was able to enhance
their electrocatalytic efficiency.

To miniaturize the electrocatalytic cell to the scale of biological cells,
the team has created custom fibers containing the positive and negative microelectrodes, which are coated with the iron sulfide nanoparticles,
and a microfluidic channel for the delivery of sodium nitrite, the
precursor material. When implanted in the brain, these fibers direct the precursor to the specific neurons. Then the reaction can be activated
at will electrochemically, through the electrodes in the same fiber,
producing an instant burst of nitric oxide right at that spot so that
its effects can be recorded in real-time.

As a test, they used the system in a rodent model to activate a brain
region that is known to be a reward center for motivation and social interaction, and that plays a role in addiction. They showed that it
did indeed provoke the expected signaling responses, demonstrating its effectiveness.

Anikeeva says this "would be a very useful biological research platform, because finally, people will have a way to study the role of nitric oxide
at the level of single cells, in whole organisms that are performing
tasks." She points out that there are certain disorders that are
associated with disruptions of the nitric oxide signaling pathway,
so more detailed studies of how this pathway operates could help lead
to treatments.

The method could be generalizable, Park says, as a way of producing other molecules of biological interest within an organism. "Essentially we
can now have this really scalable and miniaturized way to generate many molecules, as long as we find the appropriate catalyst, and as long as we
find an appropriate starting compound that is also safe." This approach
to generating signaling molecules in situ could have wide applications
in biomedicine, he says.

"One of our reviewers for this manuscript pointed out that this has never
been done -- electrolysis in a biological system has never been leveraged
to control biological function," Anikeeva says. "So, this is essentially
the beginning of a field that could potentially be very useful" to
study molecules that can be delivered at precise locations and times,
for studies in neurobiology or any other biological functions. That
ability to make molecules on demand inside the body could be useful in
fields such as immunology or cancer research, she says.

The project got started as a result of a chance conversation between Park
and Jin, who were friends working in different fields -- neurobiology and electrochemistry. Their initial casual discussions ended up leading to
a full- blown collaboration between several departments. But in today's locked-down world, Jin says, such chance encounters and conversations have become less likely. "In the context of how much the world has changed,
if this were in this era in which we're all apart from each other, and
not in 2018, there is some chance that this collaboration may just not
ever have happened."

========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by David
L. Chandler. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Jimin Park, Kyoungsuk Jin, Atharva Sahasrabudhe, Po-Han Chiang,
Joseph H.

Maalouf, Florian Koehler, Dekel Rosenfeld, Siyuan Rao, Tomo Tanaka,
Tural Khudiyev, Zachary J. Schiffer, Yoel Fink, Ofer Yizhar,
Karthish Manthiram, Polina Anikeeva. In situ electrochemical
generation of nitric oxide for neuronal modulation. Nature
Nanotechnology, 2020; DOI: 10.1038/ s41565-020-0701-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200629120213.htm

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