00;00;05;03 – 00;00;32;06
Speaker 1
Welcome to Beyond Lab Walls, a podcast from the Salk Institute. Join hosts Isabella Davis and Nicole Mlynaryk on a journey behind the scenes of the renowned research institute in San Diego, California. We’re taking you inside the lab to hear the latest discoveries in cutting edge neuroscience, plant biology, cancer, aging, and more. Explore the fascinating world of science while listening to the stories of the brilliant minds behind it.

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Speaker 1
Here at Salk, we’re unlocking the secrets of life itself and sharing them—beyond lab walls.

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Speaker 2
Welcome back to Beyond Lab Walls. I’m your host, Isabella. And today, I’m excited to talk to Dan Hollern, an immunologist and assistant professor here at Salk. Dan spent his time searching for new targets and opportunities for therapies to treat the deadliest types of cancer, blending the disciplines of computational medicine and cancer immunology in the process. I’m looking forward to learning about you, your work, and how you got into this unique intersection between disciplines, Dan.

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Speaker 2
Thanks so much for coming to talk to me today.

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Speaker 3
Thanks for having me. I’m really excited to be here.

00;01;18;05 – 00;01;23;13
Speaker 2
Okay. Let’s start at the beginning. Where were you born and where did you grow up? What was it like living there?

00;01;23;14 – 00;01;37;26
Speaker 3
I so I grew up in Grand Rapids, Michigan, and I was the oldest of seven kids. So I grew up in the midst of chaos sports and just constantly being surrounded by people and having things to do.

00;01;37;29 – 00;01;44;15
Speaker 2
Did you have any hobbies that were particularly science oriented when you were young, or was it mostly sports?

00;01;44;18 – 00;02;11;27
Speaker 3
Actually, I did have some science hobbies, although I would argue that it wasn’t totally scientific at the time, but I remember my mom to entertain us would allow us to take all the spices and the vinegar and baking soda and start to create our own like concoctions and play science. So we made a lot of messes, but that kind of got me starting to, I think, just be creative and use my imagination.

00;02;11;27 – 00;02;22;26
Speaker 3
I think that was something that really came from my my mother’s dedication to keeping us entertained as a way of keeping the chaos calm.

00;02;22;29 – 00;02;28;22
Speaker 2
So at what point in school were you thinking science was more interesting than the other subjects?

00;02;28;23 – 00;02;55;09
Speaker 3
Oh, so yeah, I really started enjoying science in high school, but I was really because I was so integrated with sports, I wanted to be an orthopedic surgeon because I had sports injuries and I was interacting with those surgeons and seeing how they helped people. And so that kind of started me thinking about human health and what’s going on, you know, sort of underneath the hood to sort of start to fix things in our bodies.

00;02;55;11 – 00;02;58;23
Speaker 2
And then when you went to college, you stayed in Michigan, right?

00;02;58;26 – 00;03;17;15
Speaker 3
Somewhat. So I went to the community college to save money. And then I went to a local college again to save money so I could sort of squat at my parents house, eat the free food. I had laundry ready to go. You know, all those those, sort of creature comforts that really make it easy to manage multiple things.

00;03;17;18 – 00;03;33;27
Speaker 3
And so, yeah, I went to undergraduate at Grand Valley State University. So that’s just about 20 minutes outside of Grand Rapids. It’s nice because you’re ten minutes from Lake Michigan, so you can hop out to the beach really easily. So that was something I did a lot for, sort of on my free time and during undergraduate.

00;03;34;00 – 00;03;39;18
Speaker 2
Did you sort of start drifting away from medicine at that point in undergrad when you were doing those advanced courses?

00;03;39;19 – 00;03;59;18
Speaker 3
Actually, it was completely different. I was really focused on that career path all the way until my grandfather got diagnosed with cancer. And when I found out what type of cancer he had, I’d never heard of it. It was angiosarcoma. It was in his scalp. And I started to learn a lot about it because my grandfather was my best friend.

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Speaker 3
He was my coach growing up in in football and also he was also somebody that helped guide me in my spiritual development because he faith was really important to him. And so he was, you know, just like my father, my anchor, and seeing what was going to happen to him with no treatment options just really devastated me and started to get me thinking, what can I do to help him?

00;04;29;00 – 00;04;52;00
Speaker 3
I realized that through starting to read the the scientific literature that’s out there, that was the path. We need people to go into science and start on that basic research, to start to tease apart what’s happening in these cancer patients, what’s limiting their therapeutic options, what options do they have if their tumors aren’t showing specific markers for an available treatment?

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Speaker 3
What can we do for those people? And so that became my mission during undergraduate. So I switched majors. And what that did for me in terms of motivation was great. After I switched majors, I four-pointed everything. I was just totally focused on that one goal. So yeah, it changed everything for me.

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Speaker 2
Did you know as soon as you switched to that goal that you wanted to go to grad school, that you want to do research?

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Speaker 3
Basically, it consumed my free time. Like because I was I was a major in biology and they only had one cancer biology course at the university. So I took that and I learned everything I could, but I realized there’s so much more going on because I was I was starting to read the primary literature. And so every day after I finish all my homework, I would have a paper and I would read it and I would take it apart.

00;05;38;23 – 00;05;58;01
Speaker 3
How did they how did they actually unlock these? So I could start to learn the scientific method, and techniques that were being used. That really drove me to graduate school. And at least knowing a little bit about how do you start to develop a research project that can make discoveries in, in cancer.

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Speaker 2
So did those childhood kitchen mixing trials accidentally translate into any real skills in the lab?

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Speaker 3
Well, I enjoyed lab work, but I was not skilled coming into the lab. In fact, that was one of the things that I remembered telling my eventual PhD mentor when I interview with him. I only had one semester of undergraduate independent research experience. I had one technique under my belt, and so what I instead told him, I said, I have a lot to learn, but you’ll never find somebody that will work as hard as me to achieve the goals of your laboratory and to learn these methods that you’re using to take apart cancers and find out why does cancer exist in these people’s bodies, and why is their body unable to contain it and remove

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Speaker 3
it?

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Speaker 2
So after that PhD you wound up in North Carolina. How’d that happen?

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Speaker 3
I ended up in North Carolina because I had I had been training in using a method that we call bioinformatics. It’s it’s basically we sequence tumors and we learn all the instructions that they’re using to, to be cancer. And when we look at those instructions and we can start to figure out, okay, where is the breakdown in information that these cells are using.

00;07;14;08 – 00;07;35;25
Speaker 3
And then we can start to identify how do we correct that. And at North Carolina, Charles Peru, who I went to work with, was famous for doing that. And he identified the intrinsic subtypes of breast cancer, which really showed that breast cancer is not one single disease. It’s many different diseases that each require a unique type of treatment.

00;07;35;27 – 00;07;49;10
Speaker 3
And so for me, learning how to do those those techniques was going to be how I was going to start to develop treatments for cancer, because I can identify what’s unique about those tumors.

00;07;49;13 – 00;07;53;10
Speaker 2
And then after that, after the postdoc what brought you to San Diego?

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Speaker 3
I wanted to end up in an institute where my science could go the farthest and my ambition to cure cancer would not be seen as something that was overly ambitious or impossible. You look at the other researchers at the Salk, they are doing their most ambitious work. So it really stands out as a research institution in the world.

00;08;18;05 – 00;08;50;17
Speaker 3
And I knew when I started to interact with the other scientists here that I had that gut feeling that if I’m going to achieve these goals anywhere, it’s going to be here because I’m going to have the backing and support of the institute and other scientists and be able to innovate with with those people to create the treatments that I want to create.

00;08;50;20 – 00;08;53;27
Speaker 2
What exactly is the kind of research you’re doing now?

00;08;53;29 – 00;09;21;18
Speaker 3
So what we’re we’re really doing is trying to understand what are the dysfunctions in a patient’s immunology or in their immune system that is preventing their immune system for from eliminating cancer. It’s estimated that every single day that we have cancer cells arise in our bodies, and our immune system takes care of it. And so, you know, what we really see with, with cancer patients is that their immune systems just don’t work properly anymore.

00;09;21;20 – 00;09;48;15
Speaker 3
And so we really want to take in that information and dissect why is their immune system not working right. And then hardwire it to start working right. And what’s amazing about doing that in our laboratory is we can see that we can actually cure tumors without chemotherapy by just solving those, those problems in the immune system and getting the immune system to again see cancer and attack cancer.

00;09;48;17 – 00;09;53;08
Speaker 2
Are you still looking mostly at breast cancer or are you looking at all cancers?

00;09;53;10 – 00;10;22;18
Speaker 3
We are. We are definitely focused on triple negative breast cancer. But what’s important about the research that we’re doing in triple negative breast cancer is it’s one of the most challenging tumor types to cure with immunotherapies. And so what I really envision is as we start to establish the fundamental principles of how do we enact a immune response against these tumors, it’s going to translate to other cancer types that have those same sort of challenges in place.

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Speaker 3
And that’s really clear when we look across solid tumors that are advanced stage, that there’s sort of a general failure of our current immunotherapies.

00;10;34;04 – 00;10;39;06
Speaker 2
Is there a reason you study breast cancer instead of another cancer type, like the one your grandfather had?

00;10;39;06 – 00;11;01;12
Speaker 3
The reason that it kind of became breast cancer is is Michigan State University, where I did my PhD. They had a really strong breast cancer research program that was for me, I looked at it as, you know, if we’re if we’re trying to solve cancer and we appreciate that everybody’s cancer is unique, that’s, that’s really present in breast cancer.

00;11;01;12 – 00;11;20;16
Speaker 3
And so if I start to learn those fundamentals and also just even how to do the research there, then I’m going to be able to pivot and attack angiosarcoma that killed my grandfather. That was kind of my plan. I knew later in life I’m going to go after this. And and that’s something that I’m really aimed at doing here at the Salk.

00;11;20;22 – 00;11;39;28
Speaker 3
I really what I want to do is get into also what are the things that cause cancer in people? Can we prevent cancer? And that’s going to be sort of the next revolution we’ve been taking apart the cancer genome, but now we’re starting to also appreciate what are these things that are happening in our bodies that are causing cancer.

00;11;39;28 – 00;11;58;09
Speaker 3
And so we now know, persistent inflammation is is one of those symbolic biomarkers that we’re at risk for cancer. So then we start to ask the question, what causes persistent inflammation in the body? And those are that’s going to sort of guide us to what are those those things that we’re exposed to that put us at risk for cancer.

00;11;58;11 – 00;12;20;06
Speaker 3
And one of the things that I’m really excited about is my my lab is developing tools to start to identify those things that are present in tumors. It’s it’s actually a lot of infectious materials. You know, it’s been well appreciated that certain bacteria cause colorectal cancer, certain viruses cause liver cancer. And so those principles are already there.

00;12;20;06 – 00;12;42;16
Speaker 3
But it’s sort of we just scratched the tip of the iceberg. The fundamentals are becoming more and more clear as to how do we correct those immune system imbalances. It’s not going to be the same mentality anymore that cancer is an impossible disease to cure, and instead it’s going to be okay. You’re going to need treatment, but you’re going to survive with this.

00;12;42;16 – 00;12;59;14
Speaker 3
Your life expectancy is not going to change. And that’s really an exciting and hopeful place to be in that we weren’t when I started my PhD. That just motivates us even even more, because we are getting after something that’s really important is going to translate to patient care.

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Speaker 2
Do you feel like it’s helpful being a part of Salk’s Cancer Center when you’re asking these questions? Like, do you collaborate often with each other?

00;13;07;14 – 00;13;30;10
Speaker 3
Yeah. We collaborate with other faculty and we’re inspired by the other faculty whose research—I have never experienced such a transformative time in my life where my perspective developed and broadened any faster or more so in a moment than when I came to Salk and started to interact with the scientists that are here and learning about what they’re doing.

00;13;30;14 – 00;14;06;23
Speaker 3
I could start to see, okay, in my laboratory, if this is true, how do I apply this concept and what are the important directions to start to go in? I think that’s been one of the really important factors in sort of that confidence that we can start to really attack this disease effectively because we have great teammates and we are in that sort of environment where inspiration is happening pretty much on a daily basis.

00;14;06;25 – 00;14;47;19
Speaker 1
If you’re enjoying this episode of Beyond Lab Walls, be sure to check out our other channels at Salk.edu. There, you can join our new exclusive media channel, Salk Streaming, where you’ll find interviews with our scientists, videos on our recent studies, and public lectures by our world renowned professors. You can also explore our award winning magazine, Inside Salk, and join our monthly newsletter to stay up to date on the world within these walls.

00;14;47;22 – 00;14;55;09
Speaker 2
I also heard you have a very fun community in your lab. I’m curious how you like being a mentor and how you kind of create that energy.

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Speaker 3
Yeah, we have we have a fun lab, but more importantly, we have a mission driven lab. I am really privileged to have talented scientists on my team that are similarly ignited by that goal of, can we cure cancer? Each person in my lab has their own story about how they’ve been impacted by cancer, and you see that in their work ethic and in their own creativity with their projects.

00;15;21;12 – 00;15;40;26
Speaker 3
I love being a mentor, seeing that growth from when this person starts to when they really start to get a handle on, what are we trying to do as a laboratory? And to see that they really embrace the goals. And then they they start to just go all out towards those goals.

00;15;40;29 – 00;15;46;10
Speaker 2
What are the kind of techniques and technologies and tools that you’re using to ask these questions?

00;15;46;10 – 00;16;29;12
Speaker 3
Technology is advanced so much that it’s even hard to keep up with each of the new platforms. But luckily we at Salk we have these advanced technologies and I also have the training and mastery of these technologies. And what they allow us to do is really take apart a tumor and also look at simultaneously the patient’s immune system’s function and identify exactly what is going wrong, what are what are the limiting checkpoints that’re stopping the immune system from attacking these cancers. And what we’ve identified as really an important factor or cell type in our immune system is called a B cell.

00;16;29;15 – 00;16;51;10
Speaker 3
And the reason that this immune cell is so important for developing new cancer immunotherapies is it’s able to basically paint a target on any type of tumor cell and mark it for destruction by the immune system. And one of the ways that it does this is with production of antibodies.

00;16;51;13 – 00;17;01;29
Speaker 2
Antibodies are large proteins used by the immune system to flag and neutralize harmful intruders in the body, like a virus or a cancerous cell.

00;17;02;01 – 00;17;26;10
Speaker 3
And these protective antibodies cover every extracellular surface. So that is that’s amazing. And so when they end by detects a pathogen, the immune system recognizes and takes care of it right away. And that’s what we’re trying to do with with cancer is, is really use these B cells to paint targets on cancer cells, amplify an immune response against it, and cause that curative response that patients need.

00;17;26;12 – 00;17;30;20
Speaker 2
And you’re using like a mouse model? Or human tissue samples?

00;17;30;21 – 00;18;02;03
Speaker 3
We use every tool that’s available to us. So we are constantly analyzing patient data, trying to understand why did this patient respond completely to their therapy? How are they able to live so long with this advanced disease versus the patients that are really susceptible to the lethality of cancer? That part has really bolstered our interest in and B cells, because these are the immune cells that are marking the most exceptional survivors of cancer with advanced stage disease.

00;18;02;06 – 00;18;25;08
Speaker 3
So they’re doing something very beneficial in those patients to keep them alive. And so now what we’re trying to do is isolate that information and then deliver that concept to new patients that don’t have those processes happening in their bodies yet. And so obviously, to develop these techniques and make sure that they’re safe, we do need effective experimental models.

00;18;25;10 – 00;18;48;07
Speaker 3
Fortunately or unfortunately, depending on how you want to look at it, mice get breast cancer, and we can use these as our experimental tools to really tease apart those fundamentals and getting the immune system to attack cancer. And we can sort of do this in a way that is still safe for patients, because we’re first ensuring that it’s going to work, that it’s not going to cause any severe side effects.

00;18;48;10 – 00;19;12;28
Speaker 3
That’s sort of like the first step in developing a treatment that can reach patients. So we first developed the preclinical data in the laboratory. And then once we identified that these these treatments are very effective, then the next stage is we need to translate that to patients. So we’re here in San Diego, we’re a basic research cancer center, but we’re also partnered with clinical cancer centers.

00;19;13;01 – 00;19;24;04
Speaker 3
And so there’s this really great opportunity to take our discoveries in the laboratory and deliver them to patients with with clinical trials that can happen at the Moores Cancer Center, for example.

00;19;24;06 – 00;19;30;01
Speaker 2
That’s very, very cool. You’re looking at B cells instead of T cells. It’s great you can have that unique angle.

00;19;30;03 – 00;19;52;25
Speaker 3
Yeah. So I think one of the important things to about the discoveries that we made that allowed us to start a laboratory at the Salk was B cells in cancer, were sort of a confusing topic. And that’s because B cells have this ability to become many different types of cells within the B cell lineage that have specialized functions.

00;19;52;27 – 00;20;14;25
Speaker 3
So there is this really confusing debate as to whether or not B cells would be advantageous as a, cell target for cancer immunotherapies.

00;20;14;27 – 00;20;45;25
Speaker 3
And when I was a postdoc, the discovery that I made was there are very specific B cell responses that we need to initiate to get these patients to respond to immunotherapy, so we know what they are now. And we know some of the principles in enacting these types of favorable B cell responses. Again, what I’m really excited about is by activating these B cell responses, we’re able to cure these these types of cancers that are often even resistant to strong chemotherapy regimens.

00;20;45;26 – 00;21;15;17
Speaker 3
In the future, we’re going to be able to give patients these therapies. And then also we’re going to be able to repair their healthy tissues from damage from chemotherapy. There’s this opportunity to not only be more effective, but also to really have it not be so disruptive to a patient’s life. And if you think about the other factor that if we’re going to be able to cure their disease, we’re also going to be able to spare them from the financial toxicity that comes with needing treatment for a very long time.

00;21;15;19 – 00;21;39;29
Speaker 3
And also the sad thing is, is the treatments are only adding years of survival. So we’re bankrupting families and only to give them a little bit of extra time. And that is that is not acceptable. And we are going to be able to use so much better in the future.

00;21;40;02 – 00;21;43;23
Speaker 2
Are there already immunotherapies that target B cells, or?

00;21;43;23 – 00;22;09;22
Speaker 3
There are immunotherapies that can indirectly activate B cells. That’s one of our standard of care regimens. But the problem is is that’s indirect. And so that doesn’t happen in every single patient. What we’ve discovered in my laboratory is there are available agents that are being applied in the clinic that haven’t previously really been appreciate it for their ability to directly activate a B cell response.

00;22;09;24 – 00;22;38;03
Speaker 3
And so now we’re using this to directly activate a B cell response. And we’re finding that this is improving the responsiveness to conventional immunotherapy, is removing resistance, both acquired and existing resistance at the start of treatment. And so now we are starting to realize okay how do we move that needle? How do we enforce a curative response? How do we take a patient that was not going to respond to treatment and move them into a response category?

00;22;38;05 – 00;23;06;06
Speaker 3
This treatment that we’re using to tease apart the basic science of how it works is already active in clinical trials, and what they’re seeing is mimicking what we’re seeing in our laboratory, that these are driving curative responses to conventional therapies by just adding this drug in. We’re getting at that starting point where the proof of concept is there and it’s repeatable.

00;23;06;08 – 00;23;23;21
Speaker 3
And then also when we study these B cells in action, going after the tumor and incinerating it, we start to see all the different molecules that are synergizing and allowing that machine to run. And so now we can start to throw a lot more gas on it, ’cause we can see what else we need to do.

00;23;23;23 – 00;23;30;10
Speaker 2
What’s on the horizon, what kind of questions are we looking forward to asking in the near and distant future?

00;23;30;13 – 00;23;51;08
Speaker 3
So one of the important challenges with curing cancer with the immune system is some cancer cells have targets on them, then allow the immune system to see them really easily. And then there are other cancer cells that don’t have a lot of targets, especially for T cells. What’s unique about B cells is they can target a lot more molecules on on cancer cells.

00;23;51;10 – 00;24;15;00
Speaker 3
We’re really focused on identifying what those targets are. So we can hardwire a B cell response to kill every single cancer cell that’s in the tumor. They really have this unique capacity. As we get creative with using these B cell responses to handle that immense complexity that cancer presents, that has really prevented us from being effective in treating that.

00;24;15;03 – 00;24;35;00
Speaker 3
So these cells are our very unique solution to the challenges that cancer is presenting us with. Once we identify those targets, which is what we’re focused on in my laboratory, we’re going to be able to ensure that a patient is going to have that same immune response to their cancer that other patients are having that allow them to survive this disease.

00;24;35;02 – 00;25;09;13
Speaker 3
I think what is like so exciting because it it we can see in the laboratory that this is this is really going to work. And there’s also other therapies that have sort of touched on this concept. And so what I believe is my, my laboratory and some of the other laboratories that are really dedicated to developing these types of treatments is going to is going to expand these, types of regimens for the different types of regimens are available and specialized to the targets on on a person’s cancer or tumor.

00;25;09;16 – 00;25;14;11
Speaker 2
It’s so exciting and promising. It really sounds like we’re at a tipping point, like you said.

00;25;14;13 – 00;25;33;23
Speaker 3
The scientists that are in my lab are going as fast and as hard as they can to sort of achieve these goals. That’s also why I have a lot of faith in our ability to start to develop these treatments is I’m not going after it by myself. I have a great team that we are aligned in the mission.

00;25;33;26 – 00;25;50;26
Speaker 3
And then also, I have a great community of scientists around me that see that mission are also similarly dedicated to it in their own way, and we are going to start to synergize together. You know, I, I work very closely with, with Sue Kaech, who is studying T cells. Now, my B cells help her T cells work better.

00;25;50;28 – 00;26;11;06
Speaker 3
And so we’re working together on okay, how do we capture that magic? How do we make sure that that happens in every single patient’s tumor? And that’s just an example of the type of environment that Salk provides us to really maximize the impact that our science can have.

00;26;11;09 – 00;26;24;10
Speaker 2
Speaking of collaborations and relationships, have you settled into San Diego, the community? What keeps you busy outside of the lab?

00;26;24;13 – 00;26;45;13
Speaker 3
Okay, so I have two major hobbies. One is I really like to exercise. I go to the gym. It kind of is my way of sort of continuing some of the things I loved about sports and challenging yourself and having mind over matter. And then the other thing I really like to do is I play guitar and also I make some digital music.

00;26;45;13 – 00;27;08;09
Speaker 3
So it’s a creative outlet for me. So every week I, you know, I go out to my guitar lessons. I used to be self-taught and then my wife for my birthday bought me lessons. So after like 20 years of playing on my own, I’m like filling in the gaps. So that’s that’s a lot of fun. And then I have, you know, I spend a lot of time hiking with my wife and my dogs, and I love San Diego.

00;27;08;12 – 00;27;26;16
Speaker 3
It’s funny, my, my, my lab found out I did music. They wanted to hear some. And they actually, I think I actually like it because they were like, can you send us some new tracks? And like when we had our lab party at the beach they were like, play some of your songs! And I was kind of like a little bit embarrassed, you know?

00;27;26;16 – 00;27;36;29
Speaker 3
But at the same time, it’s kind of it’s, it’s really great because my, I, my team and I get along so, so well. So yeah, it just makes it even more fun.

00;27;47;01 – 00;27;54;12
Speaker 2
That is, that’s very fun. I’m glad they were into the music. This has been so great chatting with you. Thank you so much for joining me today.

00;27;54;12 – 00;27;58;29
Speaker 3
Yeah, thanks for having me. This, like I said, this was a lot of fun. Love talking about our our work.

00;27;58;29 – 00;28;04;28
Speaker 2
Definitely. Thank you so much for all the work you do.

00;28;05;00 – 00;28;19;04
Speaker 2
Dan was nice enough to provide some of his own music to use throughout this episode. Thank you, Dan!

00;28;19;07 – 00;28;49;22
Speaker 1
Beyond Lab Walls is a production of the Salk Office of Communications. To hear the latest science stories coming out of Salk, subscribe to our podcast and visit Salk.edu to join our new exclusive media channel, Salk Streaming. There you’ll find interviews with our scientists, videos on our recent studies, and public lectures by our world renowned professors. You can also explore our award winning magazine, Inside Salk, and join our monthly newsletter to stay up to date on the world within these walls.