December 2, 2024 • 22 mins
Kidneys are essential for keeping the body functioning but one in seven Americans suffer from kidney disease. Alex Hughes, assistant professor of bioengineering at the University of Pennsylvania, discusses the kidney's role in the body, its structure and how his lab is working to grow new kidney tissues.
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(00:03):
This is the Discovery Files podcastfrom the U.S.
National Science Foundation.
Kidneys
are essential for keeping the bodyfunctioning by cleansing the blood,
maintaining fluid and electrolyte balance,and helping to regulate blood pressure.
But modern diets and lifestyle stressthe kidneys, which unlike the liver, bones
or skin, cannot fully regenerateor heal themselves.
(00:25):
The U.S.
centers for Disease Control and Preventionestimate that 1 in 7 Americans
suffers from kidney disease,which is progressive and incurable.
We're joined by Alex Hughes,assistant professor of bioengineering
in the School of Engineering and AppliedScience at the University of Pennsylvania,
where his lab group is workingto understand tissue development
and synthetically reconstruct new tissuesand regenerate organs in the body.
(00:48):
Professor Hughes,thank you for joining me today.
Of course. Great to be here.
I like to startwith a little bit of the background,
and I'm curious how you got interestedin biological engineering.
Right.
So actually I trained as an undergradin chemical engineering
and my interests were trendingtowards biology, but not quite there yet.
And I was lucky enough to get admittedto go to grad school at Berkeley
(01:09):
in California to do bioengineering. PhD.
And at that time,I found that it was a combination
of being drawn to but being goodat building microfluidic systems.
So a microfluidic chip
is something that where you canmanage fluids at very small volumes
and you can do measurements of proteinsor small molecules
(01:30):
very precisely, potentiallyand very high throughput.
So many things at once.
And those types of toolsare really useful for studying,
you know, proteins related to disease.
So in diagnostic settings,
but they've also become really usefulfor studying
cell behaviorsor responses of biological cells
to toxins or environmental inputsor signaling inputs.
(01:53):
And so I think naturally,
after I finished my PhD,I got moving into a postdoctoral position.
I started thinking about, okay,how can I expand my interests
to studying cell behaviorand especially collective cell behavior?
So there's so many times in biologywhere it's kind of like bees
building a hive, where simple organismsor simple cells are doing
(02:14):
amazingly beautifuland complex things together.
And yet our knowledgeabout how they're communicating,
how they're coordinatingbehavior is quite limited.
And so I became very interested in that.
Later that developed into an interestin developmental biology,
which is really a playgroundfor studying those types of things.
And that's led to where I am today.
(02:36):
I'm going to ask youto elaborate on that term there.
What is developmental biology?
It's a broad field,
but generally people are interestedin studying how organisms come about.
So during their developmental period,it's quite different to the way
that tissues operateonce that organism is an adult,
because early onyou have to start from a single cell
(02:58):
and build all the different cells
and all the different structuresin the body over time.
And so the question of how you getfrom that single cell to many, and how
they structure themselves in the right wayto do something functional,
is just amazingly complicated,beautiful and diverse.
So there's people that study this acrossmany different systems,
(03:18):
from human development to mouseto almost any type of class of organism
that you can think of.
People are studying these processes,and I think what draws people to
it is just, again,that it's a playground for studying
these complex construction processesthat cells do to take a tubule
and branch it and change the cell typesin different places.
(03:40):
And create different functionsin the heart than exist in the gut
or the liver or the kidney power,all those things specified.
So there's like the beautyof that process, and there's also
connections to other fieldslike cells often in development.
They're very invasive.They move around a lot.
There's this connections betweendevelopmental biology and say cancer.
(04:00):
And so a naive way to think about canceris that it's in some sense
cells adopting developmental behaviorsthat they shouldn't have in the adult.
It's varied.
There's a lot of people involvedand they work on different things.
And there's just it's a really excitingfield to be in right now.
And this is kind of where the stem cellspeople have heard of come in.
(04:21):
Yes, it starts off as one thingand maybe becomes something else.
And maybe you can make it becomesomething else under the right influence.
It's interesting
because Stem cells are a big partof explaining how this is possible.
You need cells that are naive enoughso they're not.
They don't have such a strong identitythat they can't be
turned into heart, or turned into kidney,or turned into liver.
(04:43):
And so a lot of people are interestedin taking stem cells.
So you take a skin cell from an adult
and you put it into a statewhere it's suggestible.
Right.
So I can suggest for it to become liversuggests for it to become kidney.
And basically those suggestionsthat we come up
with, they're usually inferredfrom development itself.
Like we might see that, okay, for a cellto become a kidney cell,
(05:06):
it has to see these three signalsin this order.
And we infer that from the embryo.
And then we try to replicate that on stemcells in a culture outside of the body.
And we cross our fingersand hope that that's what we see.
And that's been remarkably successful.
So the stem cell communityand the developmental biology community
have always been very close,if not the same, essentially.
(05:29):
You mentioned kidneys,
and your work with kidneys is kind ofwhat brought you to my attention here.
Can you talk about broadlywhat's the kidneys role in the body?
Yeah.
So the kidney, it's actually has a rangeof different functions.
So the first function right is that itfilters blood
and it allows the bodyto get rid of certain waste molecules.
(05:50):
And a lot of its focus actuallyin doing so, once you form filtrate
is that you want to grab back a lot ofuseful things, predominantly water.
And so the kidney is really this amazingtransport organ that has a filter
that's followed by a very long tubulesthat are re absorbing
and adjusting the pHand salt balance of the urine,
(06:11):
but also has some kind of otherintriguing roles.
And by no means I'm,I'm not an expert on adult kidney biology.
This is very complicated.
But it has some really interesting roles.
And for example, blood pressureregulation, and other hormonal processes.
So, it has a very strong role in adultphysiology and unexpected connections.
(06:31):
So people that have many diseases, oftenit will result in some kind of kidney
injury because it's a very sensitive organand it's very metabolically active.
So injury to the kidneys, very commonchronic kidney disease is very common.
And these affect many people.
Millions, millions and.
Millions and millions of. People. Yeah.
So I want to get into your studiesa little bit.
(06:54):
And one of them is really focusedon understanding kidney structure.
So can you kind oftalk us through that a little bit.
I'm not really sure how I ended upbeing so interested in kidney.
It was it it took a while to decide.
And I think what really capturedmy imagination are the movies
that people have made from mouse kidneysas they're developing.
(07:15):
It really just caught my imagination,and there are so many processes
happening all at once in a coordinated waythat builds the kidney,
which is effectively an organthat's just packed with tubules.
It's a transport organ, right?
It's all about managing fluid.
And so as you might imagine,there's just tubules stacked together,
like in a, you know, a water
(07:35):
treatment facility or a freshwater plantor something like that.
Right.
And so that really capturedmy imagination.
And there's processes
that are quite poorly understoodthat lead to a lot of variability.
So one thing I didn't know before workingon the kidney is that it's quite various.
People have quite a widerange of kidney function,
(07:56):
just walking aroundwithout having any disease per se.
There's a wide range of function,is a wide range and anatomical variability
between kidneys.
And so we became really interestedin understanding why that is.
And a lot ofit does go back to those early stages
when the embryo was developingthat set eventual structure. So
(08:18):
one issue with the kidney is
that there's this variability,but there's no potential after birth,
more or less for the nephrons,which are these filters to multiply.
Right.
So you can't build new nephronsas an adult.
You're kind of stuck with what you have.
And hopefully it's good enough.
And hopefully ityour function is high enough
that you don't run into issueswith disease later on.
(08:39):
Getting into the details of, say,how Nephron Number is set, we see
that is really important for understandingproblems and adult health.
Later on.
So moving into the other studythat we're kind of tied together.
You're workingat growing more of these tissues. Yes.
How is that possible?
What are you working on there. Yeah.
So as you can imagine,for such a complex organ, there's actually
(09:02):
multiple stem cells involved.
And we talked briefly about whata stem cell is.
It's cell types that can become differentdaughter lineages.
So it's known that you needat least three stem
cell types in order to build somethingthat might look like a kidney.
And one of our areas of expertise is invery precisely patterning groups of cells.
And we can make many groups at a timein different compositions.
(09:25):
So I can take, say,five stem cells and one type
and put it with five stem cellsand another type,
and build a little small community
of cells that can interactwith each other, signal to each other.
And our hypothesis was that by changingthat composition of the stem cell types
that are there,maybe we could create mini kidney tissues
(09:46):
that have different propertiesor different structures after that point.
And it's really the beginningof a much longer road
in that directionthat we can control through engineering.
But some of the first things that we sawwas that we could take stem cells
that give rise to nephronsand put them with stem cells that could
rise to the piping of the kidney,the drainage that repair the kidney.
(10:07):
And just by startingwith different compositions,
we could create mini kidneysthat have quite
different composition of the differenttubule types in the kidney.
So we were able to, in a sense,make little designer tissues and move
the needle about the decisionsthat they're making in
what particular structures they make basedon that initial condition that we set.
(10:29):
And maybeget a little insight into that role
and how it kind of comes togetherto make them so broadly different.
That's interesting.
What are the challengesgetting those stem cells to work
with each other and form the shapesyou want them to become?
Oh, it's very challenging.
And the students, you know, by no meansam I an expert and the students are.
(10:50):
I just have this wonderful capacityto learn
and to learn by doing as well,because these cells are very sensitive,
as you might imagine,because they're so suggestible.
It's almost likeif you look at them in the wrong way,
they'll become a cell typethat you didn't want, right?
And so you have to have very good skillsin the lab to be able to grow them
and take care of themand prevent them from becoming structures
(11:13):
that you don't want, propagatingthe cells, and then using very complex
and precise combinations of factorsto get them
to turn into the different typesthat you want to start from.
So in order to go into slightlydifferent lineages in the kidney,
there's a little bit of black magicabout it.
We know what some of those factors are
(11:35):
and they have to bevery precisely controlled.
So I just have a lot of respectfor students and postdocs in my lab
that can do this.
And maybe one dayI'll actually do it myself.
So what is the path
for this groundworkto become real world applications
or part of regenerative medicine like,like how does this become
(11:56):
something that helps peoplethat are on dialysis or something?
Yeah.
So I think one of the big
impacts that we can have inthe future is to address this,
you know, lack of therapiesthat we have for kidney disease.
And you touched on one of them,which is dialysis, and the other is simply
just replacing the kidneythrough transplantation.
And both of those are not ideal for a lotof reasons or just have limited capacity.
(12:20):
So there's a lot of patients
that never can never say receive a kidneyeven if they need one.
And so we have a hugefocus on understanding
what's going on and development,using it to build tissues
and then to solveremaining engineering challenges
that currently prevent usfrom taking those functional cultures
(12:42):
and putting them in the body and rescuingkidney function when we need to.
And I would say, you know, primary among
those challenges is understanding.
Again, it comes back to plumbing,like how do we take the different pieces
of the kidney that we can makeand put them together in such a way
that you have the right connectivityand flows
(13:02):
and coordinationbetween what the cell types are doing.
And that's where we thinkthe cell patterning approach can help.
Another oneinterestingly, is the vasculature.
So this is the blood flow.
Blood flow is super importantto kidney function.
And you can imagine thatif you want to put in a synthetic kidney
one of these say engineeredbiological kidneys into the body,
(13:24):
we need to properly connect itwith the blood flow of the patient.
And it's it's easier said than done.
And that's not necessarily an areathat my lab has worked on much yet.
But I think some of the work that we'redoing is pointing that direction,
whether we like it or not.
So we're starting to learn abouthow vasculature is pattern and integrated
(13:46):
with these tissues.
So still, engineering challenges to go,but 100%, our goal is to make
this have an impact in the clinicand to rescue function in so many patients
for which dialysisor transplantation is not an option
or leadsto, you know, loss of quality of life.
I'm imagining that thethe structure leading into the kidney
(14:07):
is probably also pretty uniquefrom person to person.
Yeah, actually there's not much known.
So this actually you would thinkthat human development is, you know,
it's like
if we've if we've mapped the internet,we must have mapped human development.
And that's just not the case. Right.
Because you can imagine that, havingthe right tissues and having the right,
(14:27):
it's very hard to look inside the bodyand see an embryo develop.
And that has really hamstrungsome of these research
into these questions, like, okay,it's the starting point of the kidney, but
is that just different from personto person?
Is the environment,having an effect, like,
you know, what maternal microenvironmentand aspects are there to create an arm?
(14:49):
And these thingsare studied at a clinical level,
but very difficult to studyat a fundamental level.
It's still a mystery.
But the stem cell approaches,those are helping and also studying
and model organisms such as the mousegives us a lot of information.
So I want to askabout other work in the lab.
AI is a huge area of interestfor people, right now.
Are you guys using anyAI tools in your lab?
(15:11):
Yeah.
So it's becoming hugely usefulin a couple areas.
So one of them is in basically picking outand classifying structures.
So you can use AI toolsto basically find structures
in say kidney slices or cell cultures.
And this is very usefulbecause often the task is to understand,
okay, what cells are there, what's theirmorphology, what do they look like?
(15:34):
How are they interacting with neighbors.
And these things are difficultto do manually.
And so I is really helping us to say okay,this is a nephron progenitor.
It's right next to a stromal celland it has this contact area.
So those automated image analysis
tools are increasingly using AI
(15:54):
to improve the accuracy of that annotationand expand it over many, many cells.
So we can do these kind of atlaslevel studies of cell interactions
as the cells are, you know, undergoingthese complex behaviors to build tissues.
The other area
is coding.
It's going to be interestingto see how this plays out,
(16:15):
because I'm not saying I'm, you know,at the end of my career or anything,
but I'm in this generationthat generally knows how to code,
and the AI tools can produce very accuratecoding
to help with tasks that maybe my aptitudeis not quite up to yet.
And so it's been very helpful for meto have an idea
about a model or a way of analyzing data.
(16:37):
Having the AI tool help me produce complex
code to analyze that, and then I can go and check at least my coding.
My level of knowledge is high enough
that I can go and checkwhere there might be errors. Right.
And so I think for my generationand hopefully for the next generation
of students,we can give them new ways to integrate
AI into, these coding processesthat are so important.
(16:59):
So I want to ask youabout your career award.
How has NSF support impacted your work?
Yeah.
So the NSF is
really one of the primary institutionsin the US that helps researchers
with funding to complete these typesof research projects.
You know, this is very nonlinear,and I think it's really important
for people to understandthat new discoveries, sometimes they come
(17:21):
from unexpected places. Right.
And so institutionslike the NSF are so important
for continuing supportand funding and creating new
technological advancesthat help many, many people in the US.
And so for us, we've received supportthrough it.
NSF Career Awards,
and that's really helped to funda lot of the work that we do
(17:43):
and understanding the mechanicsof development, how cells interact,
what forces do they generateand respond to.
And so, you know,I can't speak highly enough about the NSF
and what they do to supportresearch in the US.
So the last question I had for youtoday is kind of thinking ahead.
And what's next?
(18:03):
Or what are the next steps in your workhere?
Oh, so many things.
So many things.
And I you know, I'm it's just explodinginto so many, different areas.
I mean, we're really interestedin what these geometric differences
are between people'skidneys, how to explain that physically.
We're also really interested.
(18:24):
I touched on this idea that nephronnumbers are different between people,
and that seems to be correlatedwith adult disease.
So we recently have become interestedin this idea of there being a clock
or rhythm that governs the rate
of nephron production in the kidneywhen it's developing.
And so this clock has justbeen so fascinating to me, because it's
(18:46):
not just thatcells are doing this coordinated dance
to build a new filter unit, it'sthat they do it at the same time.
And there seems to bethis kind of governor that says
form one, okay, relax, formanother one, relax form another one.
And this rhythm we think issuper important for setting that number.
So we're trying to explore this in inmany different ways, both in the mini
(19:09):
kidney stem cell based approachbut also by studying the biology in vivo.
So studying mouse kidneys and seeingproteins and genes that are regulated
at different parts of this new rhythmthat we're characterizing.
There's other projects in the labthat are quite varied, like, for example,
really interested in making singlecell measurements, like measuring
(19:30):
all the proteins in single cellsvery precisely.
And that goes beyond the kidney.
That's for, you know, anybiological problem or a diagnostic problem
and other projectsthat are really directed towards
these crucial bottlenecks,like the connectivity problem,
like how do we make all of these kidneytubules connect together
at the right time, in the right placeto give you parallel function?
(19:53):
That's a big focus in the lab, too.
You know, one other aspectthat we're really excited
by is remote control of cells.
And so we have colleagues here at Penn,for example, Lucas
Pugh Guy, who are experts in a fieldcalled optogenetics.
So how can we use light to control
either gene expression or protein behaviorso that we can, in a remote way,
(20:16):
tell certain cells to do thingsand to interact with other cells?
And so we think that we could advanceupon this idea of gaining,
say, soluble signals that are inferredfrom the developing organ.
We can move beyond that and say,okay, we're actually going
to control that,you know, without soluble factors,
but using light, which you can directand you can decide when it's on and off.
(20:39):
And how often it's being activated.
That type of remote controlcould be super useful for kicking cells
between different lineages,or for inducing certain interactions.
So several people in the labare looking at ways to, for example,
optogenetic, stimulate branching
up the tubule structuresthat form a kidney.
(20:59):
And in another sense,
we could also use it to controlthis clock of differentiation of nephrons.
And so that's an emerging areathat I'm really excited about.
That's interesting.
Like I think of all of these mechanismsbeing internal.
So that light might playa role is very curious to me.
Yeah.
And that's tricky if you're tryingto operate inside the body.
(21:20):
I think the dream for usis to make a synthetic kidney,
either in a chip or in a mini kidneyorganoid system
from stem cells outside the body,where we could have that control
and we could use computersand AI to direct light activation.
But interestingly, one thing that
Lucas I mentioned is followingnow is the idea of thermal control.
(21:41):
So could we actually control cellswith temperature,
create local temperature gradientsrather than light.
And that could allow us to do these thingsdeeper inside the body as well.
Special thanks to Alex Hughes.
For The Discovery Files, I'm Nate Pottker.
You can watch video versions
of these conversations on our YouTubechannel by searching @NSFscience.
Please subscribe wherever you get podcastsand if you like our program, share
(22:02):
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Discover how the U.S.
National Science Foundationis advancing research at NSF.gov.
This is the Discovery Files podcastfrom the U.S.
National Science Foundation.
Kidneys
are essential for keeping the bodyfunctioning by cleansing the blood,
maintaining fluid and electrolyte balance,and helping to regulate blood pressure.
But modern diets and lifestyle stressthe kidneys, which unlike the liver, bones
or skin, cannot fully regenerateor heal themselves.
(00:25):
The U.S.
centers for Disease Control and Preventionestimate that 1 in 7 Americans
suffers from kidney disease,which is progressive and incurable.
We're joined by Alex Hughes,assistant professor of bioengineering
in the School of Engineering and AppliedScience at the University of Pennsylvania,
where his lab group is workingto understand tissue development
and synthetically reconstruct new tissuesand regenerate organs in the body.
(00:48):
Professor Hughes,thank you for joining me today.
Of course. Great to be here.
I like to startwith a little bit of the background,
and I'm curious how you got interestedin biological engineering.
Right.
So actually I trained as an undergradin chemical engineering
and my interests were trendingtowards biology, but not quite there yet.
And I was lucky enough to get admittedto go to grad school at Berkeley
(01:09):
in California to do bioengineering. PhD.
And at that time,I found that it was a combination
of being drawn to but being goodat building microfluidic systems.
So a microfluidic chip
is something that where you canmanage fluids at very small volumes
and you can do measurements of proteinsor small molecules
(01:30):
very precisely, potentiallyand very high throughput.
So many things at once.
And those types of toolsare really useful for studying,
you know, proteins related to disease.
So in diagnostic settings,
but they've also become really usefulfor studying
cell behaviorsor responses of biological cells
to toxins or environmental inputsor signaling inputs.
(01:53):
And so I think naturally,
after I finished my PhD,I got moving into a postdoctoral position.
I started thinking about, okay,how can I expand my interests
to studying cell behaviorand especially collective cell behavior?
So there's so many times in biologywhere it's kind of like bees
building a hive, where simple organismsor simple cells are doing
(02:14):
amazingly beautifuland complex things together.
And yet our knowledgeabout how they're communicating,
how they're coordinatingbehavior is quite limited.
And so I became very interested in that.
Later that developed into an interestin developmental biology,
which is really a playgroundfor studying those types of things.
And that's led to where I am today.
(02:36):
I'm going to ask youto elaborate on that term there.
What is developmental biology?
It's a broad field,
but generally people are interestedin studying how organisms come about.
So during their developmental period,it's quite different to the way
that tissues operateonce that organism is an adult,
because early onyou have to start from a single cell
(02:58):
and build all the different cells
and all the different structuresin the body over time.
And so the question of how you getfrom that single cell to many, and how
they structure themselves in the right wayto do something functional,
is just amazingly complicated,beautiful and diverse.
So there's people that study this acrossmany different systems,
(03:18):
from human development to mouseto almost any type of class of organism
that you can think of.
People are studying these processes,and I think what draws people to
it is just, again,that it's a playground for studying
these complex construction processesthat cells do to take a tubule
and branch it and change the cell typesin different places.
(03:40):
And create different functionsin the heart than exist in the gut
or the liver or the kidney power,all those things specified.
So there's like the beautyof that process, and there's also
connections to other fieldslike cells often in development.
They're very invasive.They move around a lot.
There's this connections betweendevelopmental biology and say cancer.
(04:00):
And so a naive way to think about canceris that it's in some sense
cells adopting developmental behaviorsthat they shouldn't have in the adult.
It's varied.
There's a lot of people involvedand they work on different things.
And there's just it's a really excitingfield to be in right now.
And this is kind of where the stem cellspeople have heard of come in.
(04:21):
Yes, it starts off as one thingand maybe becomes something else.
And maybe you can make it becomesomething else under the right influence.
It's interesting
because Stem cells are a big partof explaining how this is possible.
You need cells that are naive enoughso they're not.
They don't have such a strong identitythat they can't be
turned into heart, or turned into kidney,or turned into liver.
(04:43):
And so a lot of people are interestedin taking stem cells.
So you take a skin cell from an adult
and you put it into a statewhere it's suggestible.
Right.
So I can suggest for it to become liversuggests for it to become kidney.
And basically those suggestionsthat we come up
with, they're usually inferredfrom development itself.
Like we might see that, okay, for a cellto become a kidney cell,
(05:06):
it has to see these three signalsin this order.
And we infer that from the embryo.
And then we try to replicate that on stemcells in a culture outside of the body.
And we cross our fingersand hope that that's what we see.
And that's been remarkably successful.
So the stem cell communityand the developmental biology community
have always been very close,if not the same, essentially.
(05:29):
You mentioned kidneys,
and your work with kidneys is kind ofwhat brought you to my attention here.
Can you talk about broadlywhat's the kidneys role in the body?
Yeah.
So the kidney, it's actually has a rangeof different functions.
So the first function right is that itfilters blood
and it allows the bodyto get rid of certain waste molecules.
(05:50):
And a lot of its focus actuallyin doing so, once you form filtrate
is that you want to grab back a lot ofuseful things, predominantly water.
And so the kidney is really this amazingtransport organ that has a filter
that's followed by a very long tubulesthat are re absorbing
and adjusting the pHand salt balance of the urine,
(06:11):
but also has some kind of otherintriguing roles.
And by no means I'm,I'm not an expert on adult kidney biology.
This is very complicated.
But it has some really interesting roles.
And for example, blood pressureregulation, and other hormonal processes.
So, it has a very strong role in adultphysiology and unexpected connections.
(06:31):
So people that have many diseases, oftenit will result in some kind of kidney
injury because it's a very sensitive organand it's very metabolically active.
So injury to the kidneys, very commonchronic kidney disease is very common.
And these affect many people.
Millions, millions and.
Millions and millions of. People. Yeah.
So I want to get into your studiesa little bit.
(06:54):
And one of them is really focusedon understanding kidney structure.
So can you kind oftalk us through that a little bit.
I'm not really sure how I ended upbeing so interested in kidney.
It was it it took a while to decide.
And I think what really capturedmy imagination are the movies
that people have made from mouse kidneysas they're developing.
(07:15):
It really just caught my imagination,and there are so many processes
happening all at once in a coordinated waythat builds the kidney,
which is effectively an organthat's just packed with tubules.
It's a transport organ, right?
It's all about managing fluid.
And so as you might imagine,there's just tubules stacked together,
like in a, you know, a water
(07:35):
treatment facility or a freshwater plantor something like that.
Right.
And so that really capturedmy imagination.
And there's processes
that are quite poorly understoodthat lead to a lot of variability.
So one thing I didn't know before workingon the kidney is that it's quite various.
People have quite a widerange of kidney function,
(07:56):
just walking aroundwithout having any disease per se.
There's a wide range of function,is a wide range and anatomical variability
between kidneys.
And so we became really interestedin understanding why that is.
And a lot ofit does go back to those early stages
when the embryo was developingthat set eventual structure. So
(08:18):
one issue with the kidney is
that there's this variability,but there's no potential after birth,
more or less for the nephrons,which are these filters to multiply.
Right.
So you can't build new nephronsas an adult.
You're kind of stuck with what you have.
And hopefully it's good enough.
And hopefully ityour function is high enough
that you don't run into issueswith disease later on.
(08:39):
Getting into the details of, say,how Nephron Number is set, we see
that is really important for understandingproblems and adult health.
Later on.
So moving into the other studythat we're kind of tied together.
You're workingat growing more of these tissues. Yes.
How is that possible?
What are you working on there. Yeah.
So as you can imagine,for such a complex organ, there's actually
(09:02):
multiple stem cells involved.
And we talked briefly about whata stem cell is.
It's cell types that can become differentdaughter lineages.
So it's known that you needat least three stem
cell types in order to build somethingthat might look like a kidney.
And one of our areas of expertise is invery precisely patterning groups of cells.
And we can make many groups at a timein different compositions.
(09:25):
So I can take, say,five stem cells and one type
and put it with five stem cellsand another type,
and build a little small community
of cells that can interactwith each other, signal to each other.
And our hypothesis was that by changingthat composition of the stem cell types
that are there,maybe we could create mini kidney tissues
(09:46):
that have different propertiesor different structures after that point.
And it's really the beginningof a much longer road
in that directionthat we can control through engineering.
But some of the first things that we sawwas that we could take stem cells
that give rise to nephronsand put them with stem cells that could
rise to the piping of the kidney,the drainage that repair the kidney.
(10:07):
And just by startingwith different compositions,
we could create mini kidneysthat have quite
different composition of the differenttubule types in the kidney.
So we were able to, in a sense,make little designer tissues and move
the needle about the decisionsthat they're making in
what particular structures they make basedon that initial condition that we set.
(10:29):
And maybeget a little insight into that role
and how it kind of comes togetherto make them so broadly different.
That's interesting.
What are the challengesgetting those stem cells to work
with each other and form the shapesyou want them to become?
Oh, it's very challenging.
And the students, you know, by no meansam I an expert and the students are.
(10:50):
I just have this wonderful capacityto learn
and to learn by doing as well,because these cells are very sensitive,
as you might imagine,because they're so suggestible.
It's almost likeif you look at them in the wrong way,
they'll become a cell typethat you didn't want, right?
And so you have to have very good skillsin the lab to be able to grow them
and take care of themand prevent them from becoming structures
(11:13):
that you don't want, propagatingthe cells, and then using very complex
and precise combinations of factorsto get them
to turn into the different typesthat you want to start from.
So in order to go into slightlydifferent lineages in the kidney,
there's a little bit of black magicabout it.
We know what some of those factors are
(11:35):
and they have to bevery precisely controlled.
So I just have a lot of respectfor students and postdocs in my lab
that can do this.
And maybe one dayI'll actually do it myself.
So what is the path
for this groundworkto become real world applications
or part of regenerative medicine like,like how does this become
(11:56):
something that helps peoplethat are on dialysis or something?
Yeah.
So I think one of the big
impacts that we can have inthe future is to address this,
you know, lack of therapiesthat we have for kidney disease.
And you touched on one of them,which is dialysis, and the other is simply
just replacing the kidneythrough transplantation.
And both of those are not ideal for a lotof reasons or just have limited capacity.
(12:20):
So there's a lot of patients
that never can never say receive a kidneyeven if they need one.
And so we have a hugefocus on understanding
what's going on and development,using it to build tissues
and then to solveremaining engineering challenges
that currently prevent usfrom taking those functional cultures
(12:42):
and putting them in the body and rescuingkidney function when we need to.
And I would say, you know, primary among
those challenges is understanding.
Again, it comes back to plumbing,like how do we take the different pieces
of the kidney that we can makeand put them together in such a way
that you have the right connectivityand flows
(13:02):
and coordinationbetween what the cell types are doing.
And that's where we thinkthe cell patterning approach can help.
Another oneinterestingly, is the vasculature.
So this is the blood flow.
Blood flow is super importantto kidney function.
And you can imagine thatif you want to put in a synthetic kidney
one of these say engineeredbiological kidneys into the body,
(13:24):
we need to properly connect itwith the blood flow of the patient.
And it's it's easier said than done.
And that's not necessarily an areathat my lab has worked on much yet.
But I think some of the work that we'redoing is pointing that direction,
whether we like it or not.
So we're starting to learn abouthow vasculature is pattern and integrated
(13:46):
with these tissues.
So still, engineering challenges to go,but 100%, our goal is to make
this have an impact in the clinicand to rescue function in so many patients
for which dialysisor transplantation is not an option
or leadsto, you know, loss of quality of life.
I'm imagining that thethe structure leading into the kidney
(14:07):
is probably also pretty uniquefrom person to person.
Yeah, actually there's not much known.
So this actually you would thinkthat human development is, you know,
it's like
if we've if we've mapped the internet,we must have mapped human development.
And that's just not the case. Right.
Because you can imagine that, havingthe right tissues and having the right,
(14:27):
it's very hard to look inside the bodyand see an embryo develop.
And that has really hamstrungsome of these research
into these questions, like, okay,it's the starting point of the kidney, but
is that just different from personto person?
Is the environment,having an effect, like,
you know, what maternal microenvironmentand aspects are there to create an arm?
(14:49):
And these thingsare studied at a clinical level,
but very difficult to studyat a fundamental level.
It's still a mystery.
But the stem cell approaches,those are helping and also studying
and model organisms such as the mousegives us a lot of information.
So I want to askabout other work in the lab.
AI is a huge area of interestfor people, right now.
Are you guys using anyAI tools in your lab?
(15:11):
Yeah.
So it's becoming hugely usefulin a couple areas.
So one of them is in basically picking outand classifying structures.
So you can use AI toolsto basically find structures
in say kidney slices or cell cultures.
And this is very usefulbecause often the task is to understand,
okay, what cells are there, what's theirmorphology, what do they look like?
(15:34):
How are they interacting with neighbors.
And these things are difficultto do manually.
And so I is really helping us to say okay,this is a nephron progenitor.
It's right next to a stromal celland it has this contact area.
So those automated image analysis
tools are increasingly using AI
(15:54):
to improve the accuracy of that annotationand expand it over many, many cells.
So we can do these kind of atlaslevel studies of cell interactions
as the cells are, you know, undergoingthese complex behaviors to build tissues.
The other area
is coding.
It's going to be interestingto see how this plays out,
(16:15):
because I'm not saying I'm, you know,at the end of my career or anything,
but I'm in this generationthat generally knows how to code,
and the AI tools can produce very accuratecoding
to help with tasks that maybe my aptitudeis not quite up to yet.
And so it's been very helpful for meto have an idea
about a model or a way of analyzing data.
(16:37):
Having the AI tool help me produce complex
code to analyze that, and then I can go and check at least my coding.
My level of knowledge is high enough
that I can go and checkwhere there might be errors. Right.
And so I think for my generationand hopefully for the next generation
of students,we can give them new ways to integrate
AI into, these coding processesthat are so important.
(16:59):
So I want to ask youabout your career award.
How has NSF support impacted your work?
Yeah.
So the NSF is
really one of the primary institutionsin the US that helps researchers
with funding to complete these typesof research projects.
You know, this is very nonlinear,and I think it's really important
for people to understandthat new discoveries, sometimes they come
(17:21):
from unexpected places. Right.
And so institutionslike the NSF are so important
for continuing supportand funding and creating new
technological advancesthat help many, many people in the US.
And so for us, we've received supportthrough it.
NSF Career Awards,
and that's really helped to funda lot of the work that we do
(17:43):
and understanding the mechanicsof development, how cells interact,
what forces do they generateand respond to.
And so, you know,I can't speak highly enough about the NSF
and what they do to supportresearch in the US.
So the last question I had for youtoday is kind of thinking ahead.
And what's next?
(18:03):
Or what are the next steps in your workhere?
Oh, so many things.
So many things.
And I you know, I'm it's just explodinginto so many, different areas.
I mean, we're really interestedin what these geometric differences
are between people'skidneys, how to explain that physically.
We're also really interested.
(18:24):
I touched on this idea that nephronnumbers are different between people,
and that seems to be correlatedwith adult disease.
So we recently have become interestedin this idea of there being a clock
or rhythm that governs the rate
of nephron production in the kidneywhen it's developing.
And so this clock has justbeen so fascinating to me, because it's
(18:46):
not just thatcells are doing this coordinated dance
to build a new filter unit, it'sthat they do it at the same time.
And there seems to bethis kind of governor that says
form one, okay, relax, formanother one, relax form another one.
And this rhythm we think issuper important for setting that number.
So we're trying to explore this in inmany different ways, both in the mini
(19:09):
kidney stem cell based approachbut also by studying the biology in vivo.
So studying mouse kidneys and seeingproteins and genes that are regulated
at different parts of this new rhythmthat we're characterizing.
There's other projects in the labthat are quite varied, like, for example,
really interested in making singlecell measurements, like measuring
(19:30):
all the proteins in single cellsvery precisely.
And that goes beyond the kidney.
That's for, you know, anybiological problem or a diagnostic problem
and other projectsthat are really directed towards
these crucial bottlenecks,like the connectivity problem,
like how do we make all of these kidneytubules connect together
at the right time, in the right placeto give you parallel function?
(19:53):
That's a big focus in the lab, too.
You know, one other aspectthat we're really excited
by is remote control of cells.
And so we have colleagues here at Penn,for example, Lucas
Pugh Guy, who are experts in a fieldcalled optogenetics.
So how can we use light to control
either gene expression or protein behaviorso that we can, in a remote way,
(20:16):
tell certain cells to do thingsand to interact with other cells?
And so we think that we could advanceupon this idea of gaining,
say, soluble signals that are inferredfrom the developing organ.
We can move beyond that and say,okay, we're actually going
to control that,you know, without soluble factors,
but using light, which you can directand you can decide when it's on and off.
(20:39):
And how often it's being activated.
That type of remote controlcould be super useful for kicking cells
between different lineages,or for inducing certain interactions.
So several people in the labare looking at ways to, for example,
optogenetic, stimulate branching
up the tubule structuresthat form a kidney.
(20:59):
And in another sense,
we could also use it to controlthis clock of differentiation of nephrons.
And so that's an emerging areathat I'm really excited about.
That's interesting.
Like I think of all of these mechanismsbeing internal.
So that light might playa role is very curious to me.
Yeah.
And that's tricky if you're tryingto operate inside the body.
(21:20):
I think the dream for usis to make a synthetic kidney,
either in a chip or in a mini kidneyorganoid system
from stem cells outside the body,where we could have that control
and we could use computersand AI to direct light activation.
But interestingly, one thing that
Lucas I mentioned is followingnow is the idea of thermal control.
(21:41):
So could we actually control cellswith temperature,
create local temperature gradientsrather than light.
And that could allow us to do these thingsdeeper inside the body as well.
Special thanks to Alex Hughes.
For The Discovery Files, I'm Nate Pottker.
You can watch video versions
of these conversations on our YouTubechannel by searching @NSFscience.
Please subscribe wherever you get podcastsand if you like our program, share
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with a friendand consider leaving a review.
Discover how the U.S.
National Science Foundationis advancing research at NSF.gov.
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