A timely update on the dynamic blood-brain barrier in health and disease

Published! is a series of chats with women in science highlighting their publications as leading authors. If you know someone who has recently published a scientific manuscript who would like to chat with me, you can get in touch via Twitter @laurenpoppi or email <lauren.poppi@rutgers.edu>.

Catie Profaci is a PhD candidate from UC San Diego who studies the blood-brain barrier in the laboratory of Dr. Richard Daneman. Here, we discuss Catie’s recently published review, titled “The blood-brain barrier in health and disease: important unanswered questions” published in the Journal of Experimental Medicine in 2020. You can find the article here. We talk about the moment Catie realized she wanted to study the blood-brain barrier, its role as an ‘early domino’ in brain disease, imposter syndrome, and the project that Catie co-founded called “Stories of Women in Neuroscience”. You can subscribe to the podcast here.

The blood vessels in the brain have a number of special properties that make them different from most of the blood vessels in the rest of the body. Blood vessels in the brain have much more control over what can leave the bloodstream and enter the brain parenchyma. The structures and processes allowing for this selectivity comprise what is called the blood-brain barrier. The blood-brain barrier is critical for maintaining a healthy nervous system, by selectively controlling what ions, molecules, and even cells can and cannot enter the brain. Importantly, blood-brain barrier dysfunction is implicated in a number of diseases and disorders of the nervous system, such as traumatic brain injury and epilepsy.

What motivated you and your team to write this review?

It was an invited review. The journal had asked my advisor (Dr. Richard Daneman) if he would be willing to contribute a review. But then, in terms of the shape it ended up taking, we as a team really wanted to focus on the big questions or unknowns about the blood-brain barrier, in addition to providing information about what is known... there are plenty of reviews that do that. We as a lab continually remind ourselves that the blood-brain barrier is not just one single entity but really several different properties that are likely also dynamic in health. That’s one thing that I find particularly interesting – that we still don’t really know the range of how these properties are dynamic in health, or how they interact with the neural circuitry. Coming from a neuroscience background, that’s really interesting to me.

How was the writing process? The blood-brain barrier literature pool is massive. Was it difficult to synthesize the literature into such a comprehensive article?

First of all, I came from the Alzheimer’s disease field. So for me, the blood-brain barrier field seems smaller, or more manageable… but it is of course still really huge! I thought it was funny when you started by saying how long the review is, because it was originally four times as long.

(laughs)

There’s just so much to write about. Part of the issue is you’re not sure when you’re doing the background research what you are going to want to include in the end. So, yeah. We took the strategy of just writing way too much and then paring it down. We looked at the earlier seminal work and the newer work, and tried to balance those two, and then we just wrote way more than [we intended].

Maybe you can publish the entire thing as a full textbook!

(laughs)

I know. A lot of it will probably go in my PhD thesis.

I was wondering, after you’ve pared it down to this nice “little” article, how it was with the review process? Especially in the situation of an invited review, where [the journal] already wanted it, it’s generally a bit smoother sailing than submitting an original research manuscript. So, I was wondering how that went and what it was like?

Yes, the process was super smooth. The reviewers’ comments were really just helpful and not anything we had to argue against. Part of that is credit to the reviewers that were chosen, but I also give credit to the editor. I was previously part of another review, and that process was far less smooth. At JEM, the editor and journal staff made [the process] smoother. Of course, proofs are stressful no matter what!

I see that the Journal of Experimental Medicine places this article onto a Creative Commons license six months after its publication date. This is one of the best standards for open access. How important is it to you, now and going forward, that your work is accessible to whoever wants to read it?

I would love to continue to publish in journals that make the work accessible. I wish more of science was like that. The paywall system is really crazy to me. It was something that I took for granted before, that I could always just access papers, and then the UC system ended its agreement about a year ago with Elsevier. So, we essentially can’t access Elsevier, which is a lot of papers. I support the UC decision because they felt that the terms were not [acceptable]. For the whole UC system to think that Elsevier’s paywalls were so unreasonable speaks to such a large problem in the field. For any papers I publish going forward, if anyone emails me, I’m totally happy to share the PDF. Originally when [this review] came out, some people had trouble accessing it. I got a bunch of emails and Twitter DMs asking to send it, which I was happy to do.

This is a random question… Do you have any cool facts about the blood-brain barrier?!

Yeah so, I’m going to go old school for this one. There’s a paper from 1981 – the authors are Stewart and Wiley. They did some transplantation studies in quail and chick and found that if you take brain endothelia and put it in the gut, it becomes permeable like peripheral blood vessels, and if you take gut endothelia and put it in the brain, it develops a blood-brain barrier.

No way! That’s amazing!

So, they showed that [the barrier] is very much determined by the microenvironment rather than intrinsically by the endothelial cells themselves. After that, most people thought it was astrocytes that induced the barrier, but it turns out pericytes and signals from other cell types are more important. In the end, that’s sort of what is happening in disease. It’s not just ‘bad signals’ saying [to the blood-brain barrier] “break down!”, but it’s also missing the ‘good signals’.

That is definitely a cool fact. This was a really good transition into this next question. As you said from the beginning, we are still learning about all the different ways that the blood-brain barrier behaves in the normal situation, but also there are many things that can go wrong with the blood-brain barrier in neuropathologies like multiple sclerosis, stroke, and epilepsy, which you mention in your review. I’m wondering if you could talk about that a bit – what the significance of the “leakiness” is, what might be possible in the future for treating these conditions and others, and whether that might involve targeting the blood-brain barrier?

People who aren’t constantly inundated with the blood-brain barrier field tend to think of it as one thing, and one thing that’s either “open” or “closed”, but it’s just so much more complex and nuanced than that. It’s not that in health the blood-brain barrier doesn’t let anything in, it just has a ton of control over what specifically it lets in. What happens in disease is that it starts non-specifically letting in components from the blood that shouldn’t be there. That can disrupt the microenvironment, and neurons are so sensitive to exactly what concentrations of ions etc. are in their microenvironment – it determines how well they can function and fire. [Blood-brain barrier dysfunction] can throw off that homeostasis, but leakage of non-specific molecules can also cause the microglia (the resident immune cells in the brain) to recognize something foreign that shouldn’t be there. They can start to mount an immune response. Microglia, lots of them, start reaching out and touching endothelial cells. When the microglia are active, they can activate the endothelial cells and prime them to let more immune cells in from the blood to help fight whatever is going on in the brain. You can end up having more of an immune response than is good for your brain.

In terms of diseases and treating them… so several of the ones you mentioned – multiple sclerosis, stroke, traumatic brain injury, epilepsy. Take traumatic brain injury (TBI) for instance. It is obviously caused by something external. It is not caused by blood-brain barrier dysfunction. We like to think of these diseases as a set of dominoes. If you look at the TBI as the first domino, and the death of neurons and clinical symptoms as the end domino, we think that blood-brain barrier dysfunction is one of the early dominoes. A lot of the damage occurring in the brain is [happening] after that, so the idea is that if you could remove that early domino of blood-brain barrier dysfunction, you might be able to prevent a bunch of the clinical symptoms. You are not going to prevent the TBI, or the stroke… but maybe you could prevent a lot of the clinical manifestations that come after. Blood-brain barrier dysfunction is a common denominator in several very different diseases. You can’t get much more different from a TBI and an autoimmune disease, but they have that common denominator. We think if we could target the blood-brain barrier, we could really help [mitigate] not just one disease but several.

I remember the moment when I found something that I was really interested in, and I asked my PI at the time if I could work on it for a PhD. What first got you interested in the blood-brain barrier, and what made you decide to focus your PhD research on blood-brain barrier and glia?

I like this question a lot. I had come to grad school thinking “glia are cool, non-neural cells are cool”, but I had mainly been introduced to astrocytes and microglia. Despite doing a Bachelor’s degree and a Master’s degree in neuroscience – I didn’t come from a different field, I have been inundated with neuro from the beginning – I had not learned almost anything about the blood-brain barrier. It was not really taught in classes. Maybe neurovascular coupling, but really not anything about the cells that make up the blood vessel walls. When I was rotating in my PhD program, someone had suggested my advisor because it was a friendly lab environment and an interesting topic. So, I set up a meeting just with him to discuss my maybe doing a rotation. After that meeting, it was like (waves hands), yeah. Part of it was that I learned so much in that meeting that I had not learned in so many years of studying neuroscience. That combined with the fact that the blood-brain barrier field, I mean it’s not new, but there are still so many unanswered questions that we just haven’t had the tools to really attack yet. In general, what motivates me in research and science is the idea of solving mysteries, and there are still so many big mysteries to be solved in the blood-brain barrier field. Yeah, I was hooked from that meeting.

Something I’ve been excited to talk to you about is that you do a lot of outreach and scientific communication work. Tell us a little bit about how you got your podcast, “Stories of Women in Neuroscience”, started. I really love this podcast by the way, I’ve listened to several episodes so far and it’s amazing!

I’ve been involved throughout grad school in several outreach/sci-comm endeavours. So, in “Stories of WiN”, we interview women in academia, neuroscience, anywhere from postdoc to a senior professor. The interview audio becomes the podcast episode, and then we write the profile about the woman’s journey and accomplishments and that goes on our website. It all started when a friend from where I did my Master’s, Dr. Nancy Padilla, emailed me. She was about to move to San Diego – her postdoc lab was moving here. She emailed me saying “hey, I’ve been thinking about this idea, I just want to bounce it off you and see if you have any comments or interest in being involved”. She had come up with this idea after being on a seminar series committee. They made a list of all the people they wanted to invite, she looked down at the list and realized it was all men and thought “what did we just do?!”. The primary motivation of the project was just to increase the visibility of women in neuroscience. The secondary motivation was to have younger women who maybe are interested in the field see these role models and see that they can do something like that. So that’s how the project started. Being in San Diego for a while and already involved in sci-comm, I was able to quickly ask other people who I knew would want to be involved, and found funding, and it was born. It’s been a really great project to work on. I love all the people on the team. It’s been really inspiring to me to hear all of these stories, especially how different they all are. There’s not one way to do [academia] – you can make it work. There are a lot of different ways.

That was one of the things I loved about it. Every single episode and every person that you highlight has had a completely different experience and journey, and is a different human, you know, they love different things, and approach things differently. I found it really inspiring and really interesting to listen to. It does give you hope as well, this field isn’t always easy for a young woman, and so you listen to these stories and you think “oh, I can do it, and I can still be me, and I can be successful”.

Based on all of the work that you have done so far, and in doing your PhD, what piece of advice would you give a younger person aspiring to enter the field of neuroscience?

I think two things. One – just to emphasize that imposter syndrome is a thing that almost everyone feels, and just to normalize that a little bit more. I wish it didn’t have to be normal. I think people worry because they feel like they don’t belong, they look around at everyone else and it looks like it’s coming easy to them. I was really lucky in this PhD program, those things are talked about openly. I think it really helped me to hear before I went through it that this has a name, most people feel it, ‘imposter syndrome’ and ‘third year slump’ and all of these things. Then when it hit me, I thought “Oh, OK. This is a part of the process. This is what I’m going through.” Another piece of important advice would be that the science itself doesn’t matter as much as the mentor and the lab environment, in terms of being able to thrive and be successful. I think my experience has been really wonderful, and I think it’s largely a product of the lab environment that I chose. I could easily see myself being totally turned off by academia if I had been in a different lab environment.

Do you have anything else you would like to add?

One more piece of advice – make a Twitter! I didn’t do that until pretty late in my grad school and the network there is really amazing.

Stories of WiN was co-founded by Dr. Nancy Padilla, Megan Kirchgessner, Catie Profaci, Marley Rossa, and Dakota Blackman. We would also like to highlight Anne’s List, a list of women systems neuroscientists organized by field, first compiled by Dr. Anne Churchland to help conferences diversify their speaker lists.