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Center On Health Disparities

Chuck Harrell, Ph.D.

Chuck Harrell head shot [View Image]

This month's Mentor of the month conversation highlights the mentor-mentee relationship of Dr. Chuck Harrell and his mentee, Madelyn Esquivel.

(COHD) Dr. Harrell, how did you begin your biomedical career?

(H) I began my biomedical career as an undergraduate at North Carolina State University. I worked in a lab as an intern at the National Institute of Environmental Health Sciences, which is in Research Triangle Park, NC. I happened to get lucky and I got into a lab that worked on estrogen receptors and estrogen biology. I didn’t know what that meant or anything and they happened to make the estrogen receptor knockout mouse, which doesn’t allow the mouse to process estrogen. Since I was new at doing science, I messed up a whole lot of experiments, but eventually learned how to perform the experiments correctly, and I had a really good time learning science. I did spend one summer outside doing research related to fish mortality rates associated with hook and line and gill net fishing…but decided to go back into the human disease research labs. I got on a couple publications as an undergraduate, which was great. And, I started getting into normal mammary gland development, which also then led to some breast cancer work. My mentor there, Dr. Korach, who was a fantastic mentor, notified me about a colleague of his in Colorado – I really like spending time outdoors - that also worked on hormones and estrogens and she was known for working on progesterone, which is a hormone kind of similar to estrogen – does similar things in the mammary gland – and so I went out to Colorado, loved it immediately, fortunately got an offer to go to school there. The next day I took the offer and so I went to grad school in Colorado, and while I was there I developed a model of estrogen dependent metastasis. And so I was there from 2002 to 2007 and then in 2008 I moved back to North Carolina to work with Chuck Perou at UNC who’s internationally known for breast cancer research and he’s credited with learning about the different breast cancer subtypes. So there’s not one type of breast cancer. What he’s found is that there’s at least four different types of breast cancers and they should all be treated differently. And so while I was there I learned how to do some bioinformatic computer analysis and then combining the wet bench experience with bioinformatics tools to address questions in biology.

(CoHD) About breast cancer, most of us just think about it as one thing. But, it’s kind of like saying flowers, and there are lots of subtypes of flowers. Right?

(H) Yes

(CoHD) I didn’t realize there were only 4 kinds of breast cancer. There are probably lots more – subtypes of the subtypes.

 That’s exactly right. So there’s at least four. Some groups will say there’s 10 to 12 different types. And genetically, if you look at every single tumor, they’re all slightly different. But, if you grouped them as a family tree, you’d see 4 to 5 major different types.

(CoHD) And do you work on all of those different types, or do you focus on certain…

(H) Well, my undergrad and grad work focused on estrogen receptor positive, so that’s about 70% of all breast cancer that are ER+. And I also did some HER2+ studies and HER2 is about 10% of breast cancers. And then when I did my post-doc the lab was totally focused on triple negative breast cancers or basal-like breast cancers and so I got that one that I hadn’t really worked on very much. And the reason that my post-doc lab and my lab up until recently worked only on triple negative is because that’s the one that’s really aggressive. There are not a lot of good drugs for it. So for ER+ disease there’s Tamoxifen, which for other, newer anti-estrogens which will slow the growth of breast cancers, but for triple negative breast cancers, which are 10-15% of all breast cancers, there really wasn’t that Tamoxifen version.

Recently there’s been more progress made in Triple Negative and we’ve still got a majority of the lab working on Triple Negative breast cancers. But when Madelyn joined the lab, our first talk I was kind of pushing her to a Triple Negative project and I said, but look – there’s this whole other…

(M) At the very end, very end…

Madelyn interjecting to share what Dr. H had said to her “…at the very end, there’s these ER positive models and you could potentially help design a project with these models that are from the ground up. So think about it over the weekend." And then I came back and I was like, yeah, I’ll do the ER+ project and then you just went crazy (Dr. H – Yeah! Yeah!) All of the different information!

(H) We had had a couple of ER positive models in the lab. We hadn’t done a lot with them but I knew it was important to at least have those models and start collecting data. But you can’t spread yourself too thin. 

Especially when the people that are doing the work are like, “Yeah this is what I want to do!” And when she came in and opened it up, I said, “All right.”

(CoHD) But you had somebody who was passionate for that!!

(H) Absolutely.

(CoHD) Yeah, good fit!

(H) And so now we have a couple of those models – and we’re expanding them; we’re getting more models in that will help us study that disease better.

(CoHD) So what’s the ultimate goal of your research?

(H) The ultimate goal of my research is to provide patients – this is women and men, because men die of breast cancer too – with new therapeutic options to treat the existing metastases. Because patients with metastatic disease have a very poor prognosis and If we can develop new therapeutics to help them, that’s what I’m all about. The lab has had a couple patient advocates which are people that have or had breast cancer that have been involved in our research. They’ve read some of my grants, edited our grants. One of our patient advocates came here – I gave her a tour of the lab, she interacted with all the students – we all learned a lot about her- everything that happened from the day she was diagnosed until yesterday when I talked to her and she’s cured now. Our other patient advocate died from metastatic disease.

So the goal is really focused on treatment of metastases – that’s kind of like the end point of all the studies we do –so all of Madeline’s stuff is very upstream... But eventually we’re definitely going to try to treat metastases – what we do in the lab in a dish we then translate into mouse models of mammary tumors or primary tumors and then if we get good results then we’ll do the really hard metastasis studies.

(CoHD) Metastasis is when it moves from the breast to other organs?

(H) Right, it’s the spread of breast cells outside of the breast– anywhere else –So we very much focus on distant metastases into the liver, lung, and brain primarily. CoHD

(CoHD) And you’ve had success with some of this?

(H) Right. Over the past 22 months we’ve had 5 publications.

Out of my lab and 3 other publications where I am co-corresponding author with Jason Reed who you met last time –

We work well together – we’re funded for a couple of projects – and then there’s been other labs that we work with – I think since I’ve been at VCU I’ve had maybe 15 papers.

(CoHD) When looking at your mentees and thinking about when you were being mentored, what do you wish you would have known at their stage in your career?

(H) I wish I would have known that... well I had very good experiences for sure with my mentors – all three of my mentors were caring people – where I saw other mentors, they were caring, but they sometimes seemed to only care about the science – and they might act like they care about the student, but it’s not necessarily the case. I used to think that working in a big lab was the best thing ever – because that means they’ve got the most money and they’re the smartest people.

And then I realized that it can be a huge lab or a small lab, but if you can get the mentorship there from the postdocs there, but definitely from the PI, that’s extremely important. The PI was successful because they were smart but they also knew how to facilitate good science. And some mentors could do that and others could not.

(CoHD) But you were fortunate.

(H) I was absolutely very fortunate. As you go through graduate school, most places you have to rotate through a couple different labs before you get picked or you choose where you’re going to go – and most of my rotations were pretty good – but others I realized, that the principal investigator holds the students maybe too long, and that’s not what people want. If they need that much time to complete the project, that’s okay, so I really looked at the track record of the PI, pushing forward trying to rapidly move people along there.

(CoHD) CoHD What do you hope to gain with being a mentor and what expectations do you have from your mentees?

(M) What do I expect to gain? Well, this is a new experience for me.

(H) The lab that showed interest. And I stressed with the three of them that I spoke with that I really want someone that would consider staying in the lab after this program. Madelyn’s still on the steep learning curve and learning a lot. I’ve put a lot of energy and effort into getting them to become independent. And she’s pretty independent at this point.

We are trying to learn new things about ER positive disease – I haven’t worked on estrogen receptor positive breast cancer in 10 years and a lot has changed – the standard of care given to people who have breast cancer is totally different.

(CoHD) Describe your ideal mentor in a perfect world.

(H) I think it would involve one, providing the mentee with solid background information, a general project idea that the mentee can then run with. The mentee should be able to meet with the mentor at least once a week if not more – probably not every day that is a little too much and it puts too much of the burden on the PI to run the project – I’m really am all about pushing the students to come up with their own ideas. And to me, you’re not being a Ph.D. student if you’re not kind of off on your own coming up with your own ideas. You’re just being told to do these 10 things then you’re kind of being trained as a technician, not as a student. So initially, that needs to happen because you have to help them get that background knowledge, but eventually they kind of need to take off. So, I think that’s one important thing. I think another important thing is that the mentor provides external advisors to the student. So outside of my lab, who can they go for advice. A mentor needs to know those people. They don’t necessarily have to be only at the school so I’m really trying to utilize my network of people to help her and other people in the lab. One thing I always tell my mentees is I really want them to think 2 steps ahead in their careers. So, her goal now is to get into PhD school and earn a PhD, that’s great. But if you can think, what are you going to do after that? Start now, and then once she’s in her Ph.D. program, figuring out how to get to that next step, you’re going to be speeding things up way faster and making those contacts and things should be a lot faster.

(CoHD) Excellent.
So what do you do to relax when you’re away from the lab?

(H) I have a wife and two kids and I watch my kids play basketball and soccer and they are great swimmers. I like to cook and we like to go hiking and skiing. I might drink some beers here and there and I spend a lot of time with my family. Both me and my wife are from North Carolina, and we spend time there at the beach or Lake Gaston.

(Cohd) How old are you kids?

Dr. H They are 12 and 10.

I coach my younger son’s soccer team so that is good, because then I’m in the moment, right? There’s no thinking about getting that grant or anything like that.

(CoHD) Thank you!

(H) Thank you.

Madelyn Esquivel

Madeline Esquivel [View Image]

(CoHD) So we’re going to switch gears – Madelyn, describe your lab responsibilities.

(M) What I like is we separate responsibilities to different people. In the lab I’m in charge of basic lab upkeep, track of supplies, so we have what we need in the tissue culture room. Multiple people in the lab make sure it’s well stocked with general stuff. But I’m also responsible for ER positive models – our HCI-011 and HCI-013 lines. They’re the ER positive mice models we use, the PDX or patient derived xenograft. I’m also responsible for my personal cell lines I use for my projects. Within that there’s upkeep to maintain those lines, to have everything ready as I need it for different experiments. I also keep track of data for those experiments to compile into reports. Usually we have a lab meeting or one-on-one with Dr. Harrell, and I come with graphs or spreadsheets of my data to talk about project progression. I fit those responsibilities into when I can use the resources while working with others in the lab and learning different techniques as I need them from more senior lab members.

(H to M) I think you should explain the difference in a PDX and a cell line.

(M) PDX models match phenotypes of patients more accurately since they’re in a living system. And the mice don’t have immune systems – they’re immuno-compromised – so their immune system doesn’t attack those cells. Versus a cell line that has to adhere to plastic in a culture, so you have inherent changes in the phenotype of those cells allowing them to adhere. There’s different pros and cons of different models depending on what you are studying. If you’re using a PDX model you have to use a mouse that doesn’t have an immune system so it’s a lot harder to see how an immune system would affect different drugs that you’d use on those cells. Versus a mouse cell line with a mouse that has an immune system and you can study that. Versus cell lines that are human cell lines but adherent cells that you can grow in culture. They’re very quick to grow. They proliferate well in culture so you’re able to do a lot of in vitro studies quickly but they may not necessarily match the same results in the in vivo study, which is in the living mouse. 

(H) A lot of the cell lines that we use, including the ones she’s using have been around for 50 years. They’ve been in a lab and they’re conditioned to live and like plastic and a certain type of media. Maybe there used to be a hundred different types of cells in there. Over time they’ve gone away and there’s maybe one or two different types of cells. Whereas in these PDXs there’s 2,3,4,5 different types of cells because they’ve been maintained in a living system and they can kind of interact. The PDX models are very expensive, too.

(M) And they take much longer to grow, especially the models I use, since they are ER positive. They take around 2 months, depending on the line. It really is line specific. But the triple negative PDX lines that some of the people in the lab use go very quickly. My models grow much slower because it’s just the nature of ER positive disease. It’s faster typically to grow cell lines and it’s easier to do more preliminary results with those and then see if they’ll translate into the PDX models, since they’re more expensive.

(H) If she wanted to do an experiment with cells in a dish and we’d get the cells ready, in 10 days she could have lots of cells. But if we wanted to use these PDX models, and she’d seed the mice, then we wait 2-3 months for enough cells to then do it. There’s just this lag…

(CoHD) What do you do during that 2-3 month lag time?

(M) Cell lines! I stagger what I’m doing, so I’m always doing something. That’s one of the best things I’ve learned from this lab. Especially with what Tia, Mohamed, and some really great other higher-level people in the lab taught me. How to stagger the timing of experiments when I have down time. Even if it’s just something is spinning for ten minutes – what can I do to prep for the next step? Just for time optimization and making sure I’m not living in the lab for hours on end and not making productive use of my time. It’s a skill I’m really glad to learn from experience. The PREP program, especially working in this lab, has helped me a lot.

Being able to take that plan and see steps in the future but also maintaining flexibility, where if I get a result that I didn’t expect, I can troubleshoot or go in a different direction on that project. Or if I’m in the lab and something happens, I’m not just stuck in that moment. Being adaptable in the short term and also the long term.

(H) I want to stress we’re talking about working hard in the lab, but t’s also important to get out and not be here. I’m sure there are times when she’s thought, I’ve been in here too much. That’s when I say, okay, get out, do something.

(M) That’s one of the things that’s nice about when I first joined this lab. Dr. Harrell said, “If you’re going to be in the lab for a long time period of time for an experiment make sure you’re taking time on another day to use your time well so you can do things like go home and relax and recharge. Make sure you’re mentally ready to tackle the next problem, and not burning yourself out.” Especially since I’m a PREP student. I don’t want to burn myself out before I start my PhD, which ideally shouldn’t take more than 4 or 5 years, but that’s still 4 or 5 years that you have to devote to that science. You want to make sure you can still enjoy what you’re doing. If you’re burning yourself out by constantly being in the lab without access to sunlight, that’s probably not a good idea.

(CoHD) In the same vein, because you’re one of our PREP scholars, what are some of the benefits you’ve gained from working with Dr. Harrell and having him as a mentor?

(M) When I first joined the lab, my lab experience was mostly related to agriculture science. I was a genetics student at Texas A&M and my project focused on stallion sub-fertility. It was interesting and important because it’s a very highly expensive industry and we had a large equestrian center at Texas A&M, but it wasn’t something I could see doing for a long time. I wanted to do human based and biomedical research, so when I first joined the PREP program I was excited that we have the Massy Cancer Center here. We have so many resources to develop that side of biomedical research and get that experience. I had never worked with human cell lines before, and I definitely didn’t know what a PDX was when I joined the lab. But I knew I wanted to do something that would impact people. Breast cancer is one of the perfect things to do that because it’s one of the most common types of cancer in women in the world now. When I first interviewed with Dr. Harrell, I said this is what I want to do. I want to make sure I’m getting this experience working in basic research so I can build my resume and build my experience level to see if this is something I really enjoy. I did end up enjoying it a lot! I was also lucky that he gave me that experience, since I didn’t have previous experience with tissue culture or anything. I was able to develop that in the lab and find my niche within that research. I also enjoy that Dr. Harrell focuses on scientific communication within the lab. That was something I had struggled with previously. I knew going into the PREP program that communicating my science was something I considered a weakness. I can say that is not a weakness anymore. He’s always encouraged me to present at lab meetings to talk about my research with other people in the lab and with him and to go to presentations confidently and practice to make sure I know what I’m talking about. I had the opportunity to go to ABRCMS through the PREP program and that was really cool.

(H) And she won the poster presentation award.

(M) Yes I did win the poster presentation award! Which was nice because it was an accumulation of everything that had come together with improving my scientific communication - a big goal that I had. I was fortunate to have a mentor who pushed me to develop those skills. We had the Research in Progress presentation here – a presentation to the floor, the department of pathology – a great opportunity that a lot of PREP students don’t get. I was really glad to have the chance to try that out.

(H) The seminar series she’s talking about is once in the Pathology Department, trainees get a chance to present. These are postdocs or students who’ve been in the program 2 to 3 years usually. It’s not usual that they’ve been in the program 4 months and they’re asked to get in front of all the faculty members. She said okay, here we go and she did a great job!

(CoHD) You talked a lot about progress and having the opportunity to learn and discover and to grow. So, tell me how you’ve grown as a researcher as a result of working with Dr. Harrell.

(M) I’ve definitely increased my skill base, with tissue culture and working with biomedical research and mice, which is a huge bonus because I’d never gotten to work with those models before. But beyond that, one of the things I’ve really liked about Dr. Harrell’s mentorship style is that he doesn’t just mentor lab skills, but also project development and he makes sure I’m thinking about my own project without biasing my point of view. Sometimes, I know he has these different ideas for my current project – he’s got PowerPoints, figures, writeups and all kinds of things! But he doesn’t let me see those because he doesn’t want to bias me. If I find something I’m really interested in then I can bring it to him and say, “I think I should do this”. And sometimes we’ll be talking in meetings and I’ll say, “I think we should do this”, and he’ll say “yes, that was the thing that you should be doing”.

But he lets me get to that point on my own, which is really nice. Also, he focuses a lot in the lab on being transparent with how to be a PI and a leader within science. Like, this is how you write a grant, this is how you format a specific aims page. He explains beyond just the science that should be on the aims page, what should it look like, how should it be formatted. How can you impact people with a presentation with less words on the slide and more impactful images? How can you interact with people within multiple labs and between different PIs? How do you approach people and talk to them and say no sometimes to certain opportunities but say yes to others? Things like that I don’t think a lot of students, especially if you’re not in a PhD program, get to see. Which I really appreciate - it lets me think 1, 2, 3 steps ahead to see if that’s something I want to do later, which is nice.

(H) You should mention the single cell RNA sequencing. This might blow you away.

(M) I had the opportunity to do single cell RNA sequencing, which is fairly new to VCU. We’re the only lab right now I think that’s really doing it. It’s an expensive procedure but it was an awesome learning experience. If you look at the protocol, it’s a giant book and a little intimidating, but the level of trust letting a student take that and run with it, really work with those reagents and that expensive procedure, then get that experience was awesome. It’s something that’s going to be so valuable later in terms of running those kind of important protocols for the lab, but also in studying our PDX models further. Recently, a lot is  being done to study the heterogeneity of cancer – which is what we talked about earlier with the different cell types within the models that we use. That’s a big push right now and it’s cutting edge. I’m really grateful for the opportunity.

(H) Right now, if you went to the hospital and had a tumor, it would be biopsied and you might get some kind of molecular test done on it. When they do that test, maybe it’s 5,000 cells that they test. When they give you an answer as to if you have something like a mutation that you could treat, it’s an average of all of those 5,000 cells. There’s many different cell types and what we can do now is look at every single cell and you can clearly see that these cells look like these, and these look like this, ...

(M) …and you separate the populations out…

(H) …and we’ll do a treatment and this population will go away and this population will enlarge or a new population will come up. In the past you couldn’t see it because it was all averaged together; you could see changes, but you didn’t know at the single cell level. So, Madelyn is the third person at VCU to do it.

(CoHD) This sounds really important.

(M) It is really cool. It’s very recent but I’m really excited to get to do it.

(CoHD) So shifting gears a little bit, what do you like about VCU and Richmond?

(M) I like Richmond a lot. I live close to the medical center. I’m in walking distance to everything. I love that there’s public transport. I grew up in San Antonia TX, without public transportation. You’d drive everywhere. It’s really nice to hop on the Pulse and explore the city! I really like VCU because of the level of resources for students. It’s different than where I’ve come from, with accessibility and the time and effort VCU pours into their students. I was shocked at the level of care and commitment to the students! I know this program is only a year, but going to ABRCMS and having enough space to study, or to print something. Having those resources available when I’m not even in a graduate program yet. It’s really nice and made me feel very welcome at VCU.

(CoHD) What do you like to do when you’re away from the lab?

(M) I love to crochet and find it relaxing. I’ve also been fortunate to find a good community within Richmond outside of just VCU. I go to church every Sunday and have a family dinner with my church group every Tuesday night! We get together for a pot luck, we’ll go to the movies, hang out, go to fairs and festivals. My cohort is close, so sometimes we’ll go shopping together. We’ll just meet up and watch games or we’ve gone to the Byrd Theater a few times. I’ve been really fortunate to get a good community here beyond the lab.

 

 

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