But what really it taught me is that we have to be open-minded.
For the little bit that we know through our studies, there's just so much more that we do not know.
The human brain is the most complex structure in the known universe,
and we are in the middle of a scientific revolution to understand its inner workings.
Join us for a conversation with world-renowned neuroscientists as they visit Rochester.
I am Dr. John Foxe, Director of the Del Monte Institute for Neuroscience at the University of Rochester,
and you are listening to Neuroscience Perspectives.
I'm John Fox. I'm the Director of the Del Monte Institute for Neuroscience at the University of Rochester,
and I'm welcoming you to Neuroscience Perspectives.
I'm profoundly honored today to have a guest from the University of Wisconsin-Madison,
Professor Qiang Chen, who is a neurodevelopmentalist, a neurodevelopmental researcher, scholar, and let's start, Qiang.
Welcome to the University of Rochester.
Thank you for the invitation. Glad to be here.
It's absolutely fantastic to have you here.
Let's talk about your trajectory into science first,
and we'll get into the meat and potatoes of the science that you do fairly quickly.
You hail from China. Do you want to tell us a little bit, just like your little biography,
how you got into science, how you started out, how did you end up in the United States of America?
So I was born in Beijing, China, and I grew up in the city and stayed in the city,
go through all the schools, including college, Peking University, one of the famous ones, and never left the city.
And then the next move I made is across the ocean and coming to the United States for graduate school.
At the time, the United States was certainly viewed as the place if you want to pursue research,
pursue a science education at the highest level.
And it's a very natural move to say I want to go to graduate school in the United States,
and I was fortunate to get into University of Pennsylvania School of Medicine to pursue my PhD.
And that's where I got interested into neuroscience and got a broad training in neuroscience, neurobiology, neurodevelopment, and then went on from there.
And I think the hook there was a very interesting neurodevelopment class, and my PhD mentor, Rita Balich Gordon,
fantastic, outstanding molecular and cellular neuroscientist.
She was studying synaptic elimination using the neuromuscular junction system.
They have developed this nice imaging tool where you could label these different neurons with different color,
and then at the neuromuscular junction that synapse between muscle fiber and the neurons,
you can see the input from these different neurons, and they compete with each other,
because initially you have multiple neurons innovating a single muscle fiber, and then later on through development, you get one.
It's a one-on-one relationship. That's to ensure function. Whenever the neuron fires, the muscle contracts, you can breathe.
So that imaging experiment was really what hooked me because you could see such an intricate process right in front of your eyes,
and with this developmental trajectory and with this important functional implication.
So it's like, wow, you could do that, and the neuroscience is so cool.
So then I wanted to join her lab to study that process, and it was a really amazing journey.
Amazing. I want to pick up on two things that you said there.
One that struck me, of course, is an individual in your life that really inspired you, and you mentioned Professor Rita Balich Gordon.
And then the other piece would be arriving across the ocean, as you put it, from China to the University of Pennsylvania.
So you arrive in Philadelphia, and sort of the cultural change, and how was it navigating that?
So maybe you could speak to those two things.
To get at the first question, the first thing, my PhD mentor, I think that is quite remarkable.
When I defended my thesis, I thanked a few people. I said there's this famous saying in Chinese that for every successful man,
there's a woman behind him. So I said in my career up to this point, there are these significant people.
And I thanked my mom, and I thanked Rita. I said this is really fortunate because if you don't have that one person in your career,
of course many people, but those important moments, we're lucky to have those people to guide us and to lead us and to support us.
And I cannot say how much I'm grateful for those people along the way. So that's really, really important.
But I think what she taught me is not only how to think like a scientist, how to do critical thinking.
I think the thing she said the most to me is to get a life. Don't be in the lab all the time.
And experiments may work or may not work, and you have your frustrations, your fair share of that.
But if you don't have a life outside the lab, this is really going to be difficult for you in the long run.
So that actually saguaged into your second question really nicely, is that how I coped with the cultural change,
well, I didn't have to because at that moment we were pretty much in the lab all the time.
We didn't really go to a lot of concerts and we didn't really do a lot of these things outside the lab.
So for me, it didn't really change much. Of course, your people, your surrounding changed.
And I still remember that July the 4th concert in front of the Art Museum in Philadelphia,
where you have these incredible band playing and you have the fireworks and then you have all of these sensory inputs
all coming at you at the same time and the people around you drinking beers, dancing.
I was like, oh, so this is a really interesting experience that we never had in China.
So I mostly focused on the positive things at the get-go and then sort of spent most of the time in the lab
and didn't really have much of a life outside. It's interesting, right?
The lab provides that sort of warm space to transition. Yeah, it was really a great place.
And I really like the point that you make about Rita, who is, of course, a giant in our field
and known to many people in the neurosciences and the part of standing on the shoulder of giants.
It's these mentors that pick you up, mentor you in your science career, but also in your life.
And how to navigate the space is really, that's a beautiful story actually. Thanks for sharing that.
So let's dive into your science. I have a little of my little crib notes here.
I was wondering what role did your early work in BDNF protein play in the drug that's pending FDA approval for Rett syndrome currently?
So actually, we have a bit of unpacking to do here. We need to start with some words about Rett syndrome,
because not everybody who will be tuning in will know exactly what Rett syndrome is.
And what drew you to studying that particular disease?
Right. So this is actually a quite devastating neurodevelopmental disorder,
and it's caused by a mutation in a single gene called methyl CBG binding protein 2.
The gene is on the X chromosome, and so mostly the patients we have are girls.
And it's not that uncommon. One out of 10 to 15,000 girls, you have one Rett syndrome girl.
And when I say it's devastating, it's that in twofold.
One is the disease obviously affects many of the functions of the person, and these people are highly debilitated.
But the other aspect of this is a heart disease is that most of these girls, they are born grossly normal, so just like any other girl.
And as parents, you have a lovely daughter, and then between maybe three months to three, five years,
there is that onset of the disease that's quite sudden in that they almost feel like overnight things changed.
It's like a switch. And then these girls, they will lose many of the developmental milestones they have obtained and then just regress.
So that's a key feature of the disease. And it's very hard for people to lose something.
If you never had it, that's fine, but if you had something great and then you lost it, it's so hard to take.
So it's a heart disease. And then the way I got into the disease is a little bit by luck,
because after my PhD training, I was interested in neurodevelopment and neuroscience, how the brain works.
And I thought for my independent career, the best way to settle on important question is to find out what are the functionally most important genes.
And the way we do that is mostly in science is to take it away, use genetic approaches to remove the gene
and see whether you cause severe phenotypes. And then if you do something very important, if you don't, maybe it's not so much.
So I wanted to have a genetics toolbox. And that's where I did my postdoc with Rudolf Janisch,
really a giant in mouse genetics and many, many things. And I went to his lab to learn mouse genetic toolbox.
And the time I joined the lab, they have just made the model for Rett syndrome.
And that's a quite exciting time, I think, Huda Zoghbi's work in 1999, 2000.
That's when they identified the gene as the single cause of the disease.
And then a year later, that's when Rudolf's lab and Adrian Burr's lab, they published knockout mouse,
MECP2 knockout and mimic the disease. So that's when I joined the lab.
And then Rudolf's lab is again epigenetics, genetics. There's been neuroscientists in the lab, but not the main focus.
As a neuroscientist coming in and they have this disease model,
it's perfect for me to follow the previous postdoc's work and the study.
I suppose one of the great things about the Rett mouse model is sometimes the mouse models can be a little bit disappointing
in that they don't recapitulate the disease that we see in the human patients.
But in the case of the Rett mouse, the phenotype is very strongly similar to what we see in the patients with the midline ringing and so on.
Yeah, that's really small brain.
Gives you something to shoot at as well.
Yeah, I think we have as a field benefited tremendously from those models because if you search Rett syndrome in 2001,
you probably get double digit papers, mostly talking about the disease itself.
But now if you search, you probably got tens of thousands of papers because the field just ballooned
because the availability of those models, you have a handle, like you said.
You can really study the mechanism and then you can generate new knowledge.
So I was fortunate, again, you know, you got to be lucky sometimes to be at the right time and the right place.
And this is one of those examples.
And going back to what you're saying, my earlier work during postdoc training in the end user's lab studying the role of BDNF in Rett syndrome.
And that, again, is another teaching moment, I think, for me going into my independent career.
I have to say that's the paper actually got me a job.
But what I learned from it, it's not just the work itself.
It's more than that.
This is a gene at the time believed to be a gene that represses transcription.
And then if you don't have it, then you probably have genes whose level will go up.
And what I saw in the Rett syndrome mouse is that the BDNF level is down.
It's decreased.
This is obviously a very important neurotrophic factor.
Do you want to quickly say something about what BDNF does?
Oh, yeah. It's a brain derived neurotrophic factor.
It's a major trophic factor for the brain development and function.
And that factor being lower certainly makes sense for the disease.
There's a lot of developmental delays and sort of atrophic phenotypes.
But from the fundamental aspect, when you think of MSP2 as a repressor,
why would you have something that goes down when you don't have a repressor?
So there's a lot of debate in the field at the time when I made the observation.
I go to meetings, people ask me, well, it doesn't make sense, right?
How could you make sense of your work?
You don't have a repressor and then this gene goes down.
And it was very hard for me actually to try to discuss.
You could say, wave your hands.
This is an indirect effect and this and that.
But I think what people were questioning more is,
if you don't have something that's logical, how would it even be useful?
So how would it really make it easier to develop a therapy in the future?
So I was really thinking hard.
But BNNF is a very hard molecule to make a therapy out of in terms of the kinetics,
in terms of the pharmacological property.
And so Mir Gangar Soor at the MIT that time, who is an expert in BNNF,
and he told me, well, you know, this BNNF is never going to be a therapy.
But this general direction of trophic support is probably a valid direction.
Right, it's practical there.
Yeah, and then IGF, for example, is a trophic factor,
a growth factor that has been approved by FDA as a drug to treat something else.
You know, let's look at the general effect and try IGF-1 and see if this works.
And he actually started a collaboration with Ruel's lab to look at the role of IGF-1.
And another surprise is that, well, it did have some modest effect, but it's modest.
And then they tested the tripeptide of IGF-1, just 3-peptide of IGF-1,
known to in some cases have similar effect as IGF-1.
And they tried that in the mouse model and also had a modest effect.
There were only those two papers.
And again, the field is questioning the validity of the study.
You know, mouse work, you know, you could see effect,
but who knows whether it's going to happen in humans.
And you want to have a strong foundation of your mouse work.
And then people were saying, well, you don't have any change in expression of IGF-1.
You don't have any change of IGF-1 receptor expression in the mouse model.
How could this even work conceivably?
Right, so there's a lot of doubt.
So then, you know, what happened was because IGF-1, there's a drug available,
tripeptide, there's Neurin, a company then later on bought by Acadia.
They had a drug that's a modified version of the tripeptide, that's a truffinidide.
That's a drug now pending approval at FDA.
Because those things were all available,
and there's some preclinical data in mouse models suggesting they may work.
They just went on to do the trial.
And then the IGF-1 trial didn't pan out,
but the truffinidide trial actually gave pretty promising results.
So you can think of all of these effects as indirect.
But what really it taught me is that we have to be open-minded.
For the little bit that we know through our studies,
there's just so much more that we do not know.
So if you are certain of a result, and it's fundamentally important,
you should publish it.
You should let people see it and debate it.
Get it out there and allow it to be debated, yeah.
And let people lean on it, and that's perfectly acceptable.
And also people can do their own thing,
make their own call based on their judgment.
Pharmaceutical companies or biotech, they made their call.
They said, this is enough evidence, and we're going to try it.
Because if you didn't do those things, then you wouldn't even have a drug.
This drug, I think, really has a very, very good chance of getting approved.
Well, it must be extremely satisfying to do the basic fundamental work.
And as you say, you haven't tied it up in a bow.
There's a lot of unknowns in there.
But it gets you right to the doorstep of delivering a potential treatment
to children who need something now.
These are children who have really a severe developmental disorder.
And there's a philosophy in the two, right?
You can't wait for everything to be perfect.
Don't let perfect be the enemy of the good, right?
Yeah, yeah, that's precisely what I was going to say.
But it must be very satisfying to see this now at the doorstep of treatment in patients.
Yeah, I'm actually very excited, because in my line of work,
we interact with families as well.
I think that really, from time to time, refocuses our effort.
You have a meaning.
So what you're doing is not like three years later, it may or may not help something.
Some people are waiting, and they really need this.
And then you're making an impact with your work.
And that really is very important for me, and I'm sure for many of our colleagues as well.
Exactly.
One of the things, too, people will often ask me is that we work on Rett syndrome, as you do,
but also even considerably rarer diseases, like some of the lysosomal storage diseases.
Why are you working on a disease that impacts so few people?
Why don't you work on autism or schizophrenia?
But there's a very good reason.
Do you want to say something about that?
Obviously, for patients and their families, this is really devastating, and there's a need.
For me, there's another angle than that, which is to going back to my training,
to understand brain development and brain function.
So for me, this is a way that the system is perturbed.
And when the system is perturbed, it allows you to assess what those modulators
and those factors are doing under a physiological condition, what they do normally.
So that's an angle for me to get at how you understand this brain development and function.
And there's a lot of interesting basic functions.
This protein, for example, methyl-CBG-pyranate protein 2, it is so fascinating.
It does so many things.
People thought it was just binding to methylated Cg and be a repression of transcription,
but it does so many more things.
It's such a plutotrophic factor.
And every time you learn a new function of this protein,
you get excited about potentially learning new things about how the system works,
the brain, the neurons, and the synapses.
And one of the things we did early on unexpectedly is to find out that
this protein can be modified post-translationally by fosylation.
And that is a dynamic process, and it can be induced by extracellular signals,
depending on the cell type.
If you are a neuron, you express M-HCP2, and then the neural activity comes down the axon,
and then the neuron gets excited, and this protein in the nucleus, M-HCP2, gets fosylated.
And then it changes it properly and regulates a downstream effect through kinase pathways
and then generates synaptic changes and circuit level changes as a switch.
And then in different cell types, like neuroprogenitor cells,
this same protein is expressed, and it can be fosylated,
but this time it's triggered by a different signal, it's a growth signal.
And again, once it's fosylated at the same site,
then it triggers a different kinase pathway,
and then it has different downstream transcriptional changes and effectors,
and then the outcome would be proliferation and differentiation of that neuroprogenitor cell.
So it's a very interesting molecular switch.
And then if you think of this protein coding one-third of the genome everywhere,
it could serve as another layer of epigenetic regulation.
You know, you talk about histone code, what about an M-HCP2 fosylation code on top of that?
And then you can have finer regulation of these downstream outputs.
So that is a fascinating question that we have studied for a long time and published many papers.
And then for me as a scientist, there are all these other things we could learn,
getting in from the angle of this one disease and focusing on this one gene, this one protein.
And that's the key, right? They're monogenic diseases,
so you've got one gene that's been mutated,
and it allows you to really focus right in on a cascade of events
and a very elegant set of transcription patterns and codings and so on.
But it gives you that ability to really winnow in on a distinct problem
as opposed to trying to tackle, boil the ocean, as they say.
Oftentimes, there are insights from studying one monogenic disease
that then have implications for all the others as well,
that you learn as you go that there are mechanisms and things that are generalizable.
Yeah, precisely.
So we're going to run out of time, and I want to ask you, what's on the horizon?
What's next up for you? Where do you see the lab going and the work going over the next few years?
Well, there's a lot of work going on.
Obviously, we have these different platforms, experimental platforms like the mouse models,
the human stem cell models, and slice culture models that we could use to study this one disease
and apply on other fronts as well.
But in terms of the disease, we're actually going more into treatment or drug screening.
We have this human stem cell platform where we derive brain cell types from the patient cells,
and then we do drug screens and RNAi screens to look at molecules and genes
that could modify the disease outcome from the individual cell platform,
and then we go back to the animal models to test.
So that's certainly one major direction. There is a lot of ongoing work there.
And another direction is integration.
So obviously, we have done the genetic manipulation and looked at from the nucleus with the mutation
to the cells, to the circuit, to the animal behavior of one level at a time.
And recently, we have started work to look at multiple levels at the same time.
So I'll talk a little bit about our recent work in calcium imaging in freely behaving animals,
imaging relevant brain regions underlying certain behavior that is important for the disease,
and then basically time-lock the two modalities at the same time.
Basically, you look at the activities in the circuit.
At the same time, the animal is doing a behavior, figuring out what the animal is thinking before it does it.
So that type of integration.
And then you could do, pair that with genetic and pharmacological manipulation
to look at how these different modalities associate with each other and whether they change together.
And that's from the outside.
From inside the cells, we're doing some patch-seq experiment,
where you'll be able to sequentially look at the electrical properties of the cell
and the transcription program in that cell, and also the morphology of the cell through time and in space.
So that really gives an opportunity to look at multiple levels at the same time
and have a better understanding of the causality from one level to the next level.
So that's where we're focusing our efforts, more integrated analysis.
Of course, Rett syndrome is a focus of the lab, and a lot of the model we study has something to do with Rett syndrome.
But that allows us to broaden our research into development and developmental disorders, such as autism.
We live in a period now in the neurosciences where the tools from the molecular and cellular level
right to the systems level are so exquisite that I don't know that people really appreciate what's ahead over the next decade.
The insights that will undoubtedly come forward.
And I'm so looking forward to continuing to follow the work from your lab. It's exceptional.
I'm going to ask you one more question.
Go back to the start. I know you're a scientist, but maybe let's get a little political for a moment.
Because you were talking about coming from China to the US, where it was recognized at that time.
And this is very much the same for my own trajectory.
This was the great biomedical research engine here.
And young, talented scientists came from all over the world to here.
We live in difficult political times. We live in a time now where there's a war again in Europe.
Who would have thunk it?
And a time of tension between this great country and the great country you hail from.
Do you worry about the scientific engine and the interchange of ideas?
Do you have thoughts about that?
I do worry.
Over the last, in particular, the last couple of years, the relationship between China and the US has deteriorated.
And I think we are already seeing the impact of that.
Many of my colleagues have left the US.
And we, more importantly, have a problem with the pipeline.
And now we don't get as many Chinese students and post-docs in the labs.
Because they have viewed this political environment as not favorable.
Because when we come here, we didn't care about politics.
We had our eyes focused on science.
But now that the political environment has become so, I guess, radical, that people cannot afford to not look at it.
So many of these young people, this graduate student candidates and post-doc candidate, they turn their attention elsewhere.
So I've heard from many of my colleagues that it's in the past you post an ad for a postdoc.
A lot of those applicants are from China now.
It's not.
It will be known.
Literally right now there's none.
And I'm hoping because in science, where I am, certainly at the University of Wisconsin-Madison,
that collaborative and collegial environment, that diverse background of people is really a strength.
Because when people work together and bring your different perspective together, it actually helps science to move forward.
And that dialogue should never stop.
And the collaboration should never stop.
Because in a sense, I don't think you can do this in an isolated way.
It can be healthy competition, no doubt, and that brings the best of people for sure.
But this collaboration and cooperation really is key to doing some of these really important science work.
And it has been successful in the past.
I mean, the U.S. has been the go-to place.
And all of these talents coming in from all over the world really has helped to sustain the scientific engine in this country.
I hope that will continue to be the same way in the foreseeable future.
Because those bright minds, when you see them, you just want to work with them.
You don't view them as enemies and you want them to be on your side.
And they want to be on your side as well.
I mean, from the people of these countries, I don't really see any issues between the people.
No, but as you say, when youngsters come here to do science, it's science that they had in mind.
They weren't thinking about the politics.
And that's what has changed.
And I suppose one of the—I don't know that the American public fully appreciates how much the science engine has driven American economy
and the success of the country.
And a lot of it is on the backs of these diverse minds that came from all over the world to be here.
And one of the upshots of this is of the current political climate is that that's drying up.
I don't think people really understand that that's one of the—some of the collateral damage going on here.
Very quickly, I wanted to come back to—and it's highly related, actually.
You said something very elegant about diverse minds being the strength of a scientific engine or something along those lines.
And I know actually you serve as a leader, a chair for the diversity component of your—what's called the IDDRC.
So I think we have to explain what IDDRCs are very quickly to our audience.
Maybe you could just finish—close out, if you wouldn't mind, with some comments about your role in that—or that aspect of your role.
Right. So IDDRC stands for Intellectual and Developmental Disability Research Center.
It's a national network of research centers, and it's certainly started in the 60s.
And really, at the time, JFK, John F. Kennedy convened a committee to study the landscape.
And because at that time, people with intellectual disability, they don't get much service.
They're mostly institutionalized.
There's not much research and service going on.
And the recommendation of that presidential committee was to invest in some of these centers,
to establish some of these centers across the country to do more research,
because that's going to be the driver and the engine for discovery.
And then you will be able to provide better service and all of that.
And so now they're starting in the 60s, and 56 years later,
now we have 15 such centers across the United States.
I know you guys have one right here in Rochester, and you are the director of that center.
And that's really an amazing resource, because that really is a nucleus for each of these companies
to sort of rally the troop around the center to do research related to brain development and developmental disorders.
And this is a fantastic network, and that was born with the National Institute of Child Health and Human Development.
And basically, over 60 years, provided outstanding resource to these sites across the nation to focus on research in this area.
And in recent years, I think this network has had more collaboration,
not only at their respective sites, serve as a nucleus, but across the entire nation.
These centers have joined forces to tackle some of these important scientific questions,
because team science now is more of a mainstream now, because the questions are complex.
You're unlikely going to be able to address it with one approach. You need multiple approaches.
And then these centers are joining forces to do many things.
And one of the things the centers wanted to join forces to address is the diversity of the scientific workforce.
And of course, for the general public, diversity is a topic that needs no introduction.
I have served in the role of the co-chair of this diversity and equity inclusion workgroup across the IDDRCs.
And I think it's a really worthwhile effort when we share our experience across these sites to learn from each other what works, what doesn't,
what are the resources available, and what are the tricks you could do to increase diversity in our workforce.
And that, I think, is going to be, I guess, something we need to work hard together for quite some time
before we can see the impact, because that involves people and it's a longer timeline.
And there's many challenges there.
But I think it's really a worthwhile effort that I felt at the time quite important to work as a group.
So I volunteered to organize that group along with some other people.
And we're making some progress now, although slowly.
That's fantastic. Well, that's super important work.
I want to thank you for being here in Rochester, Dr. Chang.
It's an absolute honor and pleasure to have you. And thanks for your time here today.
Well, thank you for the invitation. I look forward to talking to your faculty here.
They do outstanding work. And that's, as a scientist, what we enjoy the most is to talk to your colleagues and learn the new things.
And then maybe some new collaborations could come out of this.
And then we will be able to do some better job back at our own laboratories after the visit.
But I think this is really a fantastic opportunity for me to be here.
Outstanding. Great to see you. Thank you so much.