A cellular message in a bottle

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{***Pause/Music***}
{***Noah***}

Coming up on Harvard Chan: This Week in Health…

A cellular message in a bottle.

{***Quan Lu Soundbite***}
(That is actually, I would say, the holy grail in therapeutic delivery)

In this week’s episode, how a new discovery about the way our cells function could pave the way for more effective drug treatments—and better tracking of diseases.

{***Pause/Music***}

{***Noah***}

Hello and welcome to Harvard Chan, This Week in Health. It’s Thursday, November 9, 2017. I’m Noah Leavitt.

{***Amie***}

And I’m Amie Montemurro.

In this week’s episode we’re delving deep into our cells to talk about some exciting new basic science research coming out of the Harvard Chan School.

The findings hinge on cellular messaging, and could have important implications for disease treatment—and may even change how public health researchers can track the impact of harmful environmental exposures, such as air pollution.

{***Noah***}

Quan Lu is Associate Professor of Environmental Genetics and Pathophysiology and he directs a lab that is mainly focused on using genetics and genomics tools, such as genome editing, to study environmental and lung diseases, such as asthma.

So for example, one area of focus involves studying a particular gene that is important to the development of asthma.

{***Amie***}

But in this episode we’re talking about something that grew out of a chance discovery in Lu’s lab.

{***Quan Lu Soundbite***}
(It’s something that grew out of this one peculiar finding in the lab. A few years ago we were looking at how cells behave under certain conditions.)

{***Amie***}

And what they found is that cells can secrete something called micro vesicles into the extra-cellular domain—basically the area that protrudes out from a cell membrane.

These vesicles are called extracellular vesicles—or EVs as we’ll be calling them throughout the episode.

{***Noah***}

Lu and his team researched a specific kind called ARMMs or “Arms”—and their work has helped explain the mechanism by which these vesicles get out of the cell.

These are ARMMs are unique because unlike other EVs, which are generated within cells, ARMMs are secreted directly from the plasma membrane at the cell’s surface.

{***Amie***}

That in itself is interesting—but Lu and his team wanted to figure out why the cells secrete these vesicles.

{***Noah***}

The reason: These ARMMS contain molecules that can be used for NOTCH signaling, which is a type of intercellular communication that normally requires cell-to-cell contact.

{***Quan Lu Soundbite***}
(We show that there’s NOTCH receptors, which sits on the surface of these vesicles. And these vesicles are able to carry these NOTCH molecules from one donor cell to another in recipient cells to initiate a very specific receptor signaling.)

{***Noah***}

According to the new findings, ARMMs are able to facilitate NOTCH receptor signaling at a distance.

And understanding more about this signaling is incredibly important.

{***Amie***}

As Quan Lu explained, humans are multi-cellular organisms—and each of our organs—the heart, the brain, the lungs are packed with cells that need to communicate with each other.

So, a cell that sits in the brain may need to communicate with the lung. And a cell in the lung may need to communicate with a cell in the liver or heart.

{***Noah***}

And biologists do know a lot about the ways in which cells signal—such as using proteins or hormones.

But the cellular messaging mechanism that Lu and his team discovered operates in a different way.

{***Quan Lu Soundbite***}
(What we suggest in our study is that these micro vesicles can signal from one cell to the other, from one tissue to the other. This is a new type of signaling. And the difference between this vesicle signaling, and say, hormone signaling, is that, for the hormone you have one molecule, say a protein or a peptide. In these small vesicles, you can imagine, they can carry many types of molecules, therefore their signaling capacity is bigger than the traditional hormones.

{***Noah***}

Because these EVs are secreted directly from the plasma membrane at a cell’s surface they have a unique ability to fuse to recipient cells.

But this mechanism also makes them uniquely suited to carry certain molecules—as Lu just mentioned—they can carry a wider variety of molecules.

{***Amie***}

He says these EVs can act as messages in bottles between cells—although it’s a little more complicated than that basic analogy.

{***Quan Lu Soundbite***}
(In fact, these vesicles not only can carry messages inside—they can proteins or nucleic acids, like RNA, DNA—but they also have a message on the surface of the vesicles. So in a way it’s more sophisticated than a “message in a bottle.” But the simple analogy, yes, they sort of use these vesicles to send messages, and the messages can be inside or outside.)

{***Amie***}
And the hope down the line is that scientists will be able to tweak what these EVs are carrying to deliver targeted “messages”—such as a drug therapeutic.

{***Noah***}

Harvard University was recently awarded two patents—based largely on Lu’s research—for technology to explore this area of research.

{***Quan Lu Soundbite***}
(So in the patents we propose that we can swap the molecules in these ARMMs vesicles with therapeutic molecular cargos. The potential advantage and scope of the application is huge. So, my lab is actively exploring these areas.)

{***Noah***}

While a potential application in a clinical setting may be a decade away, Lu says the potential uses of these findings are broad.

{***Quan Lu Soundbite***}
(If you put the anti-cancer agent in these vesicles that can be used for oncology. If you put something that would reduce inflammation in the lung inside these vesicles that can be delivered to the lung to reduce inflammation for a lot of lung diseases, such as asthma or COPD. If you put something like insulin in these vesicles, they could be used for treatment of diabetes. So, I think, as I mentioned, the scope of this application can be very broad.)

{***Noah***}

But it’s not just about changing what’s inside the ARMMS—Lu and his team want to figure out ways to target these cells to specific tissues in the body.

{***Amie***}

So, for example, when you take a drug, instead of it dispersing throughout your whole body, taking advantage of EVs could allow more targeted delivery of a drug, increasing its effectiveness, while reducing potential toxicity and other complications.

{***Quan Lu Soundbite***}
(That actually is the, I would say, holy grail, in therapeutic delivery. That you can have a broad delivery platform that can achieve tissue-specific delivery. That’s difficult, but that’s a goal)

{***Amie***}

But getting EVs to go where you want is easier said than done—and that’s a major hurdle that Lu and researchers still need to address.

{***Noah***}

Directing EVs to go to a specific tissue is something called bio-distribution. And Lu and his team are now testing this in animal models, to see if they can modify the surface of EVs to allow them to actually go into particular tissues in the body.

{***Quan Lu Soundbite***}
(So, for example, if you inject these vesicles intravenously into the animal, where do these vesicles go? Meaning, what tissues? Because, in most therapeutic delivery platforms so far, most of the therapeutics go to the liver, because that’s where detoxification is happening with all the extra chemicals injected into the body, they go through the liver. And the idea is if we can show that our vesicles can go to tissues beyond the liver, then that’s a big, big improvement over all the available therapeutics.)

{***Noah***}

One factor that makes these findings on EVs so significant is that there are so many in our bodies.

{***Amie***}

It’s estimated that we have 37 trillion cells in our body. And these cells are constantly secreting these EVs. According to Lu, it’s estimated that there are at least 100 EVs for each cell—so there could be more than 137 trillion EVs in our bodies.

{***Noah***}

But with all these EVs swirling around our bodies, how do they know where to go?

Well that’s a basic biological question underpinning much of Lu’s research—and could be the key to what we talked about a moment ago—tweaking EVs so that can be sent directly to particular tissues in our body.

{***Quan Lu Soundbite***}
(I think the best way would be to learn how nature does it. And then sort of mimic it and then you can improve upon it. But I think you need to know the basic biology first before you can jump and say “we’re going to design this, design that, engineer this, and engineer that.”)

{***Noah***}

And while we’ve talked a lot about the potential for EVs to be used for drug delivery, Lu says there is a major potential public health benefit on a broader scale.

{***Quan Lu Soundbite***}
(These vesicles could be used as novel biomarkers to track the history of disease and to track the history of environmental exposures).

{***Noah***}

Lu says molecular epidemiologists are beginning to use EVs to draw links between the development of diseases and certain environmental toxins.

There is already a body of research showing that exposure to air pollution or toxic metals like lead can affect the secretion of EVs.

{***Amie***}

And because these EVs would look different in a diseased state, it may be possible to measure the health effects of something like air pollution, not just at the individual level, but on a large scale.

So, say, for example, you draw blood from a large group of people and then measure changes in EVs to track the development of conditions like asthma or COPD.

{***Noah***}

And Lu says these findings represent a strong argument for the benefits of doing basic biological research.

When they started this area of research more than five years ago, they didn’t know about these potential benefits.

{***Quan Lu Soundbite***}
(We did not start this by saying, “We need to deliver drugs, we need to find markers, we need to look for these certain things.” But actually this project grew out of this curiosity, that cells can secrete these vesicles. We didn’t know what they are, what they do, and what implications they may have. And it was just by digging into the basic mechanisms that we realized this could potentially be very useful for a lot of things.)

{***Noah***}

Thanks to Quan Lu for taking the time to explain these really fascinating findings to us.
{***Amie***}

If you want to learn more about the work being done in his lab, we’ll have a link on our website hsph.me/thisweekinhealth.

{***Noah***}

And just a programming note that this will be our last new episode for a couple of weeks.

In the next two weeks we’ll be replaying two of our past Thanksgiving episodes.

Next week we’ll be sharing a great interview with Guy Crosby of America’s Test Kitchen focusing on the science behind the perfect Thanksgiving meal. So hopefully you’ll get some cooking tips you can use around the holidays—and year-round.

And then the week of Thanksgiving we’ll be sharing tips for having a sustainable holiday meal.

{***Amie***}

In the meantime, you can always find our older episodes by subscribing to this podcast on iTunes, Soundcloud, or Stitcher.

November 9, 2017 —In this week’s episode we delve deep into our cells to talk about some exciting new basic science research coming out of the Harvard Chan School. We spoke with Quan Lu, associate professor of environmental genetics and pathophysiology, about a newly discovered cellular messaging mechanism that could have important implications for disease treatment—and may even change how public health researchers can track the impact of harmful environmental exposures, such as air pollution.

You can subscribe to this podcast by visiting iTunes, listen to it by following us on Soundcloud, and stream it on the Stitcher app.

Learn more

Cellular ‘message in a bottle’ may path to new way of treating diseases (Harvard Chan School news)