876: Dr. Isaac Harris: Uncovering the Hidden Roles of Antioxidants in Health, Cancer, and Other Diseases

Introduction

0:00Hi, everyone. I'm Dr. Marie McNeely, and I'm excited to have you here with us for today's episode of People Behind the Science with our guest, Dr. Isaac Harris. We encourage you to visit our website at peoplebehindthescience.com to listen to some of our past episodes, find our recommended book list, and more. And we hope you'll subscribe to the show on your favorite podcast platform. Listeners, we have another excellent conversation on the way from today's guest, Isaac. So get ready to meet another one of our outstanding people behind

0:31the science. Every day, discoveries are made that will change our understanding of the world around us. Dr. Marie McNeely is here to bring you the brilliant minds who are making these discoveries so they can share their incredible stories and take you on an amazing journey. Welcome to People Behind the Science.

Guest Introduction

0:55Hello, everyone, and welcome to People Behind the Science. Today, I am thrilled to be speaking with our guest researcher, Dr. Isaac Harris. So, Isaac, welcome to our show today. How are you? Good. Thank you so much for having me on the show. I'm really excited. Well, Isaac, we are so excited to have you here with us today, and I'm looking forward to learning more about you and the wonderful work that you do. But before we get into those details, let me first take a moment to tell our listeners a little bit more about your background and how you got to

1:27where you are today. So, listeners, Isaac is an associate professor in the Department of Biochemistry and Biomolecular Sciences and the Center for Discovery and Cancer Research at McMaster University. He received his Bachelor's of Engineering degree in chemical engineering and his PhD in molecular biology from the University of Toronto. Next, Isaac conducted postdoctoral research at Harvard Medical School before joining the faculty at the University of Rochester and the Wilmot Cancer Institute in 2019. In 2024, he was awarded the Wilmot Community Outreach and Engagement Innovator Award,

2:01and he very recently moved his lab and joined the faculty there at McMaster University.

Personal Life

2:06And Isaac, in this interview, we're excited to learn more about your science, of course, but also more about you. So, can you tell us what do you like to do when you're not doing science? Nothing, nothing too crazy. So, I have a wife and a five-year-old kid, and so I like spending time with them. I like cooking. I like really just relaxing, watching TV with my wife and reading books and stuff like that. Pretty poor. I'm not climbing any mountains, right? I like that in my free time.

2:38That's fair. I thought you were going to stop at nothing. And I was like, I too enjoy the art of doing absolutely nothing. Wonderful. So, what are some of your favorite activities to do with your five-year-old lately? Really, whatever she wants to do. She can do dictates. So, coloring, playing outside, going to the park, eating ice cream, and I'm sure I'll change next week and just try to chase her around and do cool stuff. And I started watching 90s Simpsons with her, and that was fun. So, I'm

3:12slowly getting into introducing her to the channel to TV that I enjoyed.

Book Recommendations

3:18Oh, wonderful. Well, it's great to get some insight into your life outside the lab. You mentioned you enjoyed reading as well. That's something we love talking with guests about on the show and getting book recommendations from everybody. So, Isaac, do you have a favorite book that you've read at some point, or even just a recent one that you've really enjoyed that you want to tell us about today? Definitely fiction, like horror, like Stephen King, the Dark Tower series. I recently really read a book called The Fisherman. It was like a horror kind of drama. I don't know if you've heard that one.

3:49That one was really, really cool. I think recently I've been reading Christopher Buhlman. He does a lot of horror stuff and sci-fi horror, stuff like that. Excellent. Well, we will put some of these recommendations on our website for our listeners to find if they're looking for something a little bit spooky to read. And we've talked about your

Research Overview

4:10life outside the lab. I'd love to talk about your science as well. You're doing some really cool research. So, how do you describe it to people who aren't familiar with your specific work or are perhaps outside of science altogether? We study the roles of antioxidants in health and disease. And one thing that's unique with our research is that most people outside of research have heard of antioxidants. It's definitely in the public domain. I think you can turn on the TV and here you should be taking antioxidants and antioxidant supplements. But really, my research is trying

4:45to uncover and pull back what this actually means. What are antioxidants? How are they made? How are they used? And ultimately, how do they impact disease? And really, a big part of it is that when they've actually done clinical trials, we study cancer as a disease. And as it pertains to

Antioxidant Research

5:04antioxidants, there's been a public perception that antioxidants, these antioxidant supplements can have a cancer prevention role, especially these people selling these supplements and so forth. So, back in the 2000s, they actually did a clinical trial to show how antioxidants could prevent cancer. They looked at men in their 50s. They're monitoring prostate cancer. And at the time, it was the largest cancer prevention trial ever undertaken. It was like 400 centers, 135,000 men. And unfortunately,

5:38they had to stop the trial. So, whenever I talk about my research, I always lead with this because this came out when I was in grad school. It really was a pivotal study. And the interesting thing is, like, and I'll ask you, like, why would you stop a clinical trial, especially a cancer prevention clinical trial? And why do you think that? Well, there are a number of reasons. One, there could be some, like, detrimental side effects that are coming up. People are having some sort of unexpected consequence of taking the treatment. Two, they're actually getting more cancer than the people who are in the control groups. Yeah. So, it's actually the second one because they've

6:13been proven not to be toxic and harmful and they're sold everywhere. But the study met futility, meaning there was no way it was going to prevent cancer. And the only way you could 100% know it's not going to prevent cancer if it was actually promoting cancer. So, there was this trending increase that men taking vitamin E, this really potent antioxidant, were getting more cancer. And then a further study came out later where it was highly significant. So, this really kind of blew my mind

6:45when I was a grad student where it was like, wait, this is a very clear clinical evidence to show that antioxidants might be doing the exact opposite as what we think, that they could actually be in some instances in these supplements and especially in these high doses, they could be promoting cancer. So, then my research really wanted to look inside the cell and inside the body and say, okay, we take away all these supplements and we just look, how does the cell make its antioxidants? Can we actually

7:17figure out a way of stopping cancer or slowing its growth? And that's really been my research is understanding how the cancer cell uses these antioxidants and makes them. And ultimately, if we can block these pathways, can we slow or prevent cancer growth?

Cancer Research

7:35Well, Isaac, I think this is absolutely fascinating. I think you're absolutely right. This idea of antioxidants has sort of been popularized in the public as a generally good thing, but I think dose matters. And I'm really glad you mentioned that point because oftentimes the dose that you'll get in just sort of eating normal foods is very different from what you would get from taking a supplement. Yeah, in my opinion, that's exactly true. Again, I'm not a clinician, but I think it gets really tricky because this whole supplement industry is largely unregulated. It's not through clinical trials.

8:08And again, the clinical trial that they've done really showed the opposite. So, when we're talking fruits and vegetables, these are such complex entities that you're consuming vitamins and you're consuming so many different things. And I think it's really different to say, OK, we're going to pull out one part of it. We're going to amplify it by 2000 percent and put it into a pill and sell it to you. And then it's going to say it's natural. It's like, well, sure, it's natural, but there's so much

8:39about it that's unnatural. Like you said, the dose, how it's delivered in an isolated form, all these things is not natural. These are all synthesized. So, I think that's a really important thing to appreciate that there's so much clinical evidence that demonstrated that fruits and vegetables and a healthy diet is very much preventative of cancer. That's very clear. But I think where you get into this very unclear zone and what we're trying to clarify is that is what happens with

9:10the dosing and the delivery and specifically different types of antioxidants. That makes sense. Well, I look forward to chatting more about your research as we go through our conversation. And I think just in general, being excited about the work that you do in science can be very motivational. But do you have a particular quote or a saying or a force,

Motivation and Quotes

9:28Isaac, that keeps you motivated when you're having a tough day? So, I have a lot of quotes. I realized that this is a podcast and there's no visual element to it, but I actually have a lot of quotes up on my wall. And I've had different quotes for different times, I think, in my career. And so, early on, like I remember hearing later means never. I have that up. I had everyone wants to be a bodybuilder, but no one wants to lift these heavy weights. But I tried to call it. And in terms of just being like this science requires sacrifice and hard

10:04work. I think more recently, the one quote I've looked towards is, I don't know if you know the quote from Dune, I must not fear, fear is the mind killer. No, I've not watched Dune. So, it's based on a blog. It says, I must not fear, fear is the mind killer. Fear is the little death that brings total obliteration. I will face my fear. I will permit it to pass over me and through me. And when it is gone past, I will turn the inner eye to see its path. Where the fear is gone, there will be nothing. Only I will

10:37remain. I feel like I say that quote to kind of like calm me down, I guess. A lot of times, if it's before a big meeting, a difficult conversation, because I feel like a lot of at least my anxieties come from fear, come from unknown. And if we're able to identify the fear and understand what it is, you know, it's nothing that I think we can move past it. Well, I love these quotes, Isaac. And I think you're right. This idea of overcoming fear, overcoming rejection, I think, in science, these are very, very important lessons. And they are

11:11difficult. And I don't think they necessarily even get easier as you go through your career. They don't get it. That's like back to the bodybuilder. It's not like lifting weights ever gets easy. And if it gets easy, then you're going to want a bigger weight. And there's that quote from, I think, the CEO of NVIDIA, where it was like, to pain and suffering, you know, there's growth or there's learning. And I think that's such a big thing where it's like, we can't fear rejection, we can't fear failure, we can't fear the truth. And ultimately, trying to embrace that is going to

11:44as hard as it is, for myself, has led to any growth I've had in life. It's been through faith and failure and growing from it.

Inspirational Figures

11:53Definitely. Well, fantastic quotes. We will put them on our website for our listeners to find there as well if they're looking for some inspiration. And I'd love to hear a little bit more perhaps about the people who've inspired you across your career path. So Isaac, do you have particular mentors or role models or just inspirational figures that you've looked up to? First and foremost, my parents, they were obviously my closest and most influential people in my life. They worked very, very hard. They also just taught me everything. And just in terms of if you want to

12:24go after something, it's going to take hard work and sacrifice. In research, I have a lot of people that definitely inspire me. First being my PhD supervisor, Dr. Tak Mak. He really shaped a lot of how I view science. Also my postdoctoral mentor, Dr. John Brugge. She taught me aspects of rigor, collaboration, collegiality. Both my PhD and postdoc mentor taught me that the importance of trying to do the best

12:57science possible and ask the biggest questions possible. And then really starting off, I think one figure that jumped out was Terry Fox. I don't know if you've heard Terry Fox. No, I have not. So I'm Canadian. So Terry Fox was a Canadian. So basically he grew up, he played sports and then he went to school. And then in school, he ended up having a knee injury and it turned out he had cancer in his knee and his cancer. He had to get amputated above his knee. And while going through

13:27treatment, he was like, wow, this is really bad. And it's bad for me, but it's really bad for a lot of other people. The treatment, the cancer treatment, everything. So he decided if he was to make it all the treatment, he would want to raise money for cancer research. And so he started a foundation where he was like, I'm going to run across Canada. And this was like insane because this is before social media. This is, I forget the exact date, but this is back in the 70s. He died in 1981. And so in the

13:5870s, he's like, I'm going to run across Canada to raise money. And I'd always kind of known a bit about him, but in starting to do cancer research, I read more about him. And so, yeah, he basically ran a marathon a day for months. That's amazing. He started on the east side in Newfoundland and then he made it about halfway to Ontario, just at the edge of Ontario. And then unfortunately the cancer came back and he wasn't able to finish it. But this led to a foundation that's raised nearly a billion

14:30dollars for cancer research in Canada. And so it's a really, I think, inspirational story to everyone across the world. This is literally a person that just said, I'm going to do this and I'm going to do what's in my power. And he did it. And he has a lasting legacy that's led to new discoveries and ultimately new treatments for people. Well, I think that is absolutely amazing. And it sounds like a really inspiring story, both for people who are interested in researching cancer and having that opportunity to get funding through this foundation, but also just cancer patients. Seeing someone really

15:05rally and try to support the cause to help people who will come after him. Yeah. And I think it kind of puts in perspective how, I think a big thing when I started cancer research, I was doing a Hepha-Princess Market Hospital and this was a hospital with patients going to get treatment. And a big thing in science is for people to, whether it be cancer research or any disease, is to understand that we're doing this for a purpose. We're not especially basic research. We have no deliverable. We're trying to advance the knowledge, advance science. This is basic,

15:38basic research. What are we doing? We're trying to make these discoveries that ultimately can change the outlook for people with diseases such as cancer. And so to understand what we're fighting, you know, what we're going for, why we're doing this, and also to put into perspective how hard it is for people with these different diseases and to understand it, we have to keep going. Absolutely. Well, it's wonderful to hear about these inspirational and motivational figures that have had a big impact on you. And you mentioned your parents from the very beginning were very

16:09supportive. I'd love to talk about those early years for you. So can you share, how did you first

Career Path

16:14get interested in science and begin on this career path? So the career path came later. Career path came probably when I was in university, but I think early on, again, now that I have a daughter. So my father did an undergraduate degree in chemistry and geology, and he would always take us out, he would call it rock hunting. So we would go look for different rocks and different fossils and different types of rocks. And I think that was probably one of

16:45the earliest memories of scientific discovery is just stuff like that. He got us one of these like small microscopes where it'd have a mirror to reflect, like a really small microscope. And we had microscope slides, he would do science experiments at home, like the vinegar and baking soda, explosions, stuff like that. So I was really, really privileged and fortunate to have early on, like the joy and excitement of science and discovery. You think like rock hunting, it's like,

17:16what do you do? But you're just outside and you're picking up rocks and you pick up one. You're like, oh, there's none, no. I think that translates a lot to my job now in research where there doesn't have to be a lot of thought put into. A lot of this is just discovery. A lot of this is we're trying different experiments and we're seeing what's happening and it takes a long time and this, and no one goes rock hunting necessarily and says, okay, I have everything planned out. I'm going to do this and this and all. I know this part. And it's like, no, you just go and it's

17:47just discovery. And I think not really seeded in me really early, the joy of discovery. And growing up, my parents really pushed getting a job, working. And I had a lot of jobs that were very labor intensive. I worked two summers on the groundskeeping of a summer camp. And it was like nine hour days, six days a week. And you would just, I was like a janitor, groundskeeper, a cop person. And I also had a lot of opportunities. I think this is really important in terms of

18:17learning, work, professionalism, showing up, getting stuff done. And I think that carries over to science immensely. Also being okay with being bored, I guess. Painting a side of the shed or picking up garbage, just manual labor. Mundane tasks, but it's really, really critical to my growth because I was comfortable in those mundane tasks. And getting comfort in that really translated to, because again, the stuff with science, I think it's sometimes portrayed as this

18:48romantic discovery and glamour. A lot of it's just grinding. Right. Mundane tasks. A lot of it's just grinding. And these discoveries don't always come from a eureka moment. They usually come from just not giving up. Just keep trying no more time. We're going to try one more experiment. We're going to try something else. So that, I think, was also really influential in my career development. Definitely. It sounds like the geology, of course, didn't stick. Can you talk about then maybe how this

19:18transition to biology came to be? So coming out of high school, I wanted, like most, to be a doctor. I'd watched all the TV shows. I really was fascinated about the human body and treating people. But then I remember my father's like, well, if you go and do an undergraduate study and you don't get into med school, then you have nothing to fall back on. The only thing you could do is research. He was like, why don't you do an engineering degree? This is a professional faculty. And at least without, you could get a job after.

19:49If you don't get into med school. So I started in chemical engineering and I really, really liked it. And it was really formative in terms of, again, developing problem solving skills, teamworking skills, communication skills, understanding that you can break down a problem if you just take time and try to think deeply about something. So I was doing chemical engineering. In my first year, actually, I started learning about research and I was like, wow, this is really crazy because it's very different than being a doctor because there isn't that immediate, you're

20:24not working with the patient, you're not working with the person, there isn't that response of someone saying thank you. But there's the opportunity that if you do discover something and if you do work hard enough, you can really contribute towards helping a lot of people well beyond your immediate circle or your immediate span. And you could really influence people across the world. And so I really got excited about that. So I shifted from engineering to biology and biomedical sciences because the research

20:54and engineering, how I viewed it, it was very much engineering. It was designing drug delivery systems, encapsulation of pharmaceuticals, formulations. And that was interesting, but I started to learn about biomedical science and I was like, wow, this is detective work. This is investigatory. And I love detective books, Michael Connolly and James Ollar. And I started to get, I'd be like, wow, I can take my problem solving skills that I've learned in engineering and I can try to apply it to very basic questions.

21:26And during my undergraduate studies, what really started all of this was I met my PhD mentor, Tach Mac. I connected with him immediately. And one thing he said to me that always stuck with me is, you have to remember what you're doing, the questions you're asking, no one has ever asked them before. That's always stuck with me. And in terms of research, I kind of got hooked. I was like, wow, I'm able to ask these questions that no one's asked before. I'm able to get the answer before anyone in the world. And I think biomedical research, at least it can be a pretty existential

22:00pursuit because you say, okay, the discoveries are out there, but it's up to me to find them. So with TAS, with the odd, you kind of say, okay, let's go for it. That's awesome. So you stayed there at the University of Toronto for your PhD, and then you decided to go to Harvard for your postdoc. Can you talk about that decision, what your experience was like? So I was finishing my PhD in studying antioxidants and the roles in cancer. And I really wanted to keep studying. I had many more questions. And I also, a big part, like career trajectory,

22:35lots of times is you got to leave home. You got to go somewhere else. And it's also a massive opportunity to build your network and really learn new skills, new techniques, and be exposed to new ideas. And so I wanted to go somewhere else, but I still wanted to really study antioxidants. And so investigator Joan Brugge, she put out a paper in 2009, 2010, really showing antioxidants had this role in supporting breast cancer growth. So it was one of these studies that I read a million times,

23:07and I cited and influenced my work. And so then, again, I think a big thing with science is you can meet your heroes, but then you can actually work with them and learn from them and train from them. And so I ended up meeting Joan. I remember I read all of her papers and she was visiting the institute in Toronto and the administrative assistant, they're bringing food. She's part of a scientific advisory board. And the administrative assistant was like, hey, Isaac, can you help me

23:38bring some food over to the lunch thing? So I helped bring some food over. And then, and she's like, oh, you should say I have some food. So like, yeah, okay, cool. And then I saw Joan was there and she was there. And I was like, I got to talk to her. This is my one opportunity. I need to talk to her. And I said, hey, I love your paper and this. And we started talking and then we met at a conference and we kept talking. And then I was like, look, I really want to do a postdoc. She was like, I'm not taking anyone right now. And then at some point I was like, hey, I'm going to be in Boston.

24:08Can we have a coffee or something? She was like, yeah, sure. Why don't you come and just give a talk and interview? And so the truth was I wasn't going to be in Boston. I just said that. And then I said, oh, I guess I'm going to Boston. And I had a friend at MIT and I slept on his floor. And then I stayed at the YMCA on LinkedIn and then I interviewed. It went great. So I think it was also a thing where there's always opportunities to make opportunities. I had to push a little bit

24:39and maybe I had to go a bit roundabout way, but ultimately it really worked out. Well, I love this story, Isaac. I think it's a testament to your tenacity and not taking no for an answer sometimes if you have that dream and know what you want. And I think that's really important in science, just that persistence and that kind of sticking with it. And then I know the transition from postdoc to faculty is often another sticking point or a challenge for scientists. Can you talk about what that search experience was like for you? In my opinion, me going to do a postdoc in Boston is equivalent of an actor going to Hollywood, being like, I'm going to make it big.

25:14And not everyone that goes to Hollywood makes it out. So there was a lot of pressure, especially with science. The deliverables sometimes take longer. Sometimes they come sooner, but sometimes they take longer. And so my paper was not published yet. I was in my sixth year. We had a really good story and we were just resubmitting, but I said, okay, I need to take a shot at this. I went into my postdoc saying, I want to come out with an independent position. I want to have my own lab. And that alone was, it's all scary, especially when you say it out loud. And once you have a goal, it sets you up for

25:50failure. So that is always a bit scary. But I had this immense support from my supervisor. She just supported me every step of the way. She allowed me the freedom to develop my ideas independently, along with her support. She helped shape them in terms of different directions and saying, maybe don't do that or maybe do this. So that was huge. So I had her support. I put out a lot of applications. And then this one came up at Rochester and it was amazing because I never

26:21thought I would be here in Rochester. And Rochester is a really, really interesting place. It's kind of the way I describe it is like East Coast progressiveness meets Midwest community. It's kind of this mix of a lot of really great people, really great science. So yeah, I jumped at it and the last seven years have been amazing. And yeah, now I'm really excited for my next stage at McMaster. Definitely. And I know you're in the midst of a transition at the moment, but I'd love to talk about your work. I know the lab at McMaster is not yet set up, but can you tell us a little bit more

26:56about your current research and if there's a particular project that you're working on or one that you've finished recently that you're just the most excited about? One of the ones that we just recently published a couple months ago in Nature was taking a very deep look at this one antioxidant glutathione. We've studied it for quite some time and it's the most abundant antioxidant in the cell, most abundant in the body. And it's made up of these three amino acids, glutamate, cysteine, and glycine. So these three amino acids form glutathione and

27:31glutathione is really the cysteine that acts as the antioxidant part of glutathione. So we've always looked at and lots of people have looked at glutathione being antioxidant. But one thing we started looking at was what if it actually has more roles than just being antioxidant and maybe does it have unexpected roles? And so one of those we started looking at was that the glutathione outside the cell, it can actually be broken back down into its individual amino acids,

28:02glutamate, cysteine, and glycine. So cysteine is one of these amino acids. It's one of the most precious amino acids. It's in the catalytic site for many proteins or their enzymatic activity. And it's incorporated almost into, I think, 98% of proteins. So in all of our studies, we have seen that there's glutathione as an antioxidant and there's all these other antioxidant pathways, the theridoxins, theridoxins, catalase. But what was unique about glutathione was that it could be

28:33broken back down into these amino acids. And so we started to say, like, maybe it has this other role of just being a storage unit of these amino acids or a storage unit even for cysteine. So we started to look at how we grow our cancer cells. And how we grow them is we feed the individual amino acid. We actually feed this oxidized form of cysteine, cysteine. And so we said, well, if we switch out the individual, instead of giving the cancer cells cysteine, if we just get glutathione, would they

29:06be able to break it down and use it? And it turned out to be true. The cancer cells could in fact break down and use the glutathione and use the cysteine from the glutathione to grow and survive. One really big thing was we actually looked inside tumors. And so there's liquid. So we always try to get as close to reality as possible with our experiments. And so lots of times people have done work to profile or identify the different metabolites in the blood and the serum. But more recently, people have realized

29:38there's actually a liquid interstitial of the tumor. So like basically liquid that exists in between the different cells within tumors. And so they call it this tumor interstitial fluid. So we found that if we actually profile this, if we look at the metabolites in there, there's actually a lot of glutathione. So that started to tip us to say, okay, maybe there's way more glutathione outside the cell than we realized. We started to do experiments to show that cancer cells could in fact use this glutathione

30:11as a source of amino acids. And then finally, we said, okay, if we take these tumors grown in vivo and in animals, if we blocked the breakdown of glutathione, could we slow cancer growth? And this was the case. We could see that by stopping the enzymes that break down the glutathione back into these individual amino acids, we could actually deprive the tumor of this amino acid cysteine and ultimately slow tumor growth. And so this we're

30:42really, really excited about because it really changes how we view antioxidants. I think how we view this one antioxidant glutathione, but also how we view the different food sources for tumors and for cells in our body. I think it's been potentially overlooked a bit that these resources for the tumors are far more complex than we realize. So this is one thing we're really excited to go into and to see, okay, is there far more to this in terms of the cancer cell relying on these different dipeptides or two amino acids

31:17together or tripeptides like you've found, three amino acids? Are they relying on these? And if we block this, can this be a really new approach to slowing or stopping cancer growth? Well, Isaac, I think this is fascinating research. And I think the findings, as you mentioned, are really exciting and they have a lot of potential to shape the field of cancer research. And not just that, but it opens the door for different ways to potentially treat cancer as well. That's exactly it. I think there's new drug targets. There's entirely new pathways we're trying to pull

31:49apart. We're also trying to look at, is there unexpected antioxidants that we haven't even realized? You know, a big thing in my old supervisor attacking is to say, and we really try to do this, is you can ask old questions with new technology. And the technology really has been advanced and it's continuing to be advanced. And so we're trying to do this. We're trying to ask that glutathione was discovered more than a hundred years ago in the 1800s. But we're still just trying to understand what it does. And is there other antioxidants like it and what they do? And so I think it really

32:25shifts our ability to potentially control or stop cancer growth. And this kind of goes into a lot of different directions. One being our diet. What are we consuming? And even outside of supplements and stuff like this, how can we tailor our diet to best meet all our needs, but also limit these excess amount of antioxidants or amino acids? And so we've shown that shifting to a plant-based diet is one approach that you can take to actually lower the amount of these amino acids in your body and

32:58potentially starve the cancer from these excess amino acids. We think that there's approaches to study this in terms of diagnosing cancer. The idea that cancer cells use this pathway that use glutathione and use it as amino acid sources really opens potentially new ideas towards developing probes that actually identify and pinpoint different cancers and visualize them in your body. And then again, finally, it's just to make new discoveries. These biochemical textbooks have been developed decades and

33:31decades ago. And I think that there's a lot of room with any technology to re-interrogate this and to re-analyze it. Again, I kind of go back to my training and engineering in physics and stuff like this, where it's like there's multiple answers to a question. There's multiple different ways you can attack it. So I think to kind of look at biology and say there's actually way more to the story and we can re-interrogate these pathways and potentially come up with very new answers.

34:01Oh, definitely. And I know, Isaac, that this project has gone really well in the context of

Current Research

34:06science. And I think that's not always the case. So let's talk about some of the failures and the challenges, because I think it's not always these eureka moments every day in science like it's portrayed in the media. So do you have a struggle or a challenge that you can tell us about? I have a lot. We do a lot of studies in animals. A lot of these experiments, especially a genetically engineered mouse model, could take years to set up the experiment and then you get the result and there's no difference. One example, we're really interested in this one enzyme that supported

34:40antioxidants. We found that there was a mouse available in a lab in Japan. We emailed the person, they agreed to send it to us, they sent it to us, we bred the mice, we bred it to the tumor model, and then we aged them. And then we look and there's no difference. This is like a years long experiment. And so I think you have to have a pretty short memory with your failure. There's stuff you want to remember that you don't repeat them, but especially stuff like this, when you're taking a

35:11shot and trying to ask something, you kind of just have to say, okay, I guess there's no difference. And we have learned something, there is no difference. And there's a lot of importance in getting these, you know, quote unquote negative results, but you have to keep going and you have to face these challenges. I always remember my supervisor, Tack, when I first said I'd heard a talk from this person, Dave Tuveson, showing work of Gina DeNicola. And I was like, this is so, I really want to study this. I want to study antioxidants. And I remember Tack at the time,

35:45when I was just studying grad school, and he looked at me and he went to his computer and he went to PubMed and he wrote antioxidants answer. And he clicked it and 5,000 papers came out. He goes, you really want to do this? What are you going to do different? So that was a challenging thing where he challenged me. He said, well, if you're going to do something, you better be doing something different. That theme has come up a lot. Studying something that's been studied for so long are inherent challenges to convince people there's more to be studied.

36:15We've had so many failures in terms of grant applications and people say, this has already been studied. Move on, do something else. Well, sometimes you got to move on, do something else, but it's also, this isn't new criticism. I think there's a lot of importance of asking these old questions and reinterrogating these pathways. Definitely. And always challenging those assumptions to make sure they still hold true with the best technology. Well, Isaac, thank you so much for walking us through some of these

36:46challenges that you face in your work. I think it's so important for people to get a realistic view of what life is like in science, but we don't just want to dwell on the tough times. Do you have a favorite success story you'd like to share with us? I think more recently in being a supervisor, during PhD and postdoc, you have opportunities to supervise. You can work with undergraduate students, you can work with technicians, and these have been amazing experiences. I'm seeing these people grow and go on to grad school. So there's not a technician that just graduated from Sloan Kettering. I remember during my grad school,

37:21I mentored an undergraduate. She went to Australia and is in biotech. But probably one of the best successors was my first graduate student here in Rochester. This was during COVID. So I started my lab in the fall of 2019. So about six months after starting the lab, everything kind of came crashing down. But we say, OK, we have to keep going. We have to keep going. And I had an opportunity for the student, Gloria, to join and she joined. And it was just one of the best experiences because to fully mentor someone

37:55and try to help their career and build up the lab, build a collegial environment, build an environment where people are supportive of each other and to really see as a mentor where it's like, I can't change people, but I can try to help them and I can try to help them view different perspectives and I can put them in front of people. And with the student, it was just really cool to see that when this person totally bought in, they ended up having a great publication in Nature Communications, ended up getting a job at Roche out in Arizona and they're still there and they're incredibly successful there.

38:31And so seeing that entire Ph.D. development, especially during pretty tricky times of COVID, that was, I think, a really huge success story and it continues to be, in my opinion. Absolutely. I think just this idea of being part of the journey of the next generation of scientists is a really cool aspect of the job. I think it's important for people like I am an advisor. I can give you advice. Yes. So sometimes she would say, what do you think we should do? And I'd be like, well,

39:02it's your project. You got to tell me what you think we should do. And then she had more and more confidence. And then eventually it was a point where I would suggest stuff and she's like, no, we shouldn't do it like that. No, no, no. Do you want to do it right or do you want to do it wrong? And I was like, OK, cool. And so helping people train, being part of the ride, also giving people space to grow and fail on your own. I always say everyone has to accept failure, but it's important to also realize that as a supervisor,

39:33you also have to accept that they're going to go through this. It's not going to be everything is going to be smooth and it's going to be up and downs. And to just kind of stay the course and keep going and trying to provide that support to say, like, it's OK, let's keep going. So it taught me a lot. And also I can look back and be like, all right, this was an incredible experience and I really like doing this. Another really important experience has been also training people within my lab and trying to support them is also helping support people outside the lab. And so during the

40:06pandemic, actually, me and a colleague, Gina DiNicola, started this virtual conference called the Cancer Metabolism Showcase and Workshop. And it was really because a lot of these in-person conferences were canceled. So we started this in 2022 and it really took off. And we've had this amazing experience of bringing together leaders in the field, but ultimately it's called the Showcase and Workshop. And so it's the showcase because all the speakers of this conference are

40:37non-faculty members. They're either PhD students or postdocs or technicians. So we're really trying to showcase the next generation, the new trainees, the new people coming out of this field of cancer metabolism. And it's also called the Workshop because on both days, it's a two-day conference, we provide these workshops. So day one, we have a workshop on building skills, networking, science communication, and several others. And then day two, we have workshops about moving towards your next step. And so preparing for academic job search, going from PhD to postdoc, going into

41:12industry, all these different things. And so it's a really, in my opinion, great forum. It's accessible. It's free. There's no travel. There's no cost associated with it. We do it on this platform called GatherTown where you have this little avatar and you walk around and we have a poster session that each year is amazing. This year, it's going to be September 8th and 9th. In the fall, we have an amazing keynote speaker, Ralph Debertinias, who's one of these leaders in the field of cancer metabolism. So yeah, I just wanted to kind of also share that and put that out there.

41:46Everyone can check it out at cancermetabolismshowcase.org. Then I can include this information, but that's also been a really great experience I've had over the years. Well, Isaac, this sounds like an amazing event. Thank you to you and your colleagues for putting it together. And of course, congratulations, Isaac, to you and your trainees. And I think this aspect of mentorship is a really rewarding part of the career. And I think one of the other things that's really rewarding or enjoyable are some of the opportunities that you get to travel and to meet people from all over the world. So can you talk about some of your scientific travel and maybe in

42:20particular, if there was one place that was just the most memorable for you? It's interesting. I'm traveling a lot more now than I ever did before, but it was the travels I did before that meant the most to me. So as a graduate student, a graduate student in salary, you don't have this extra income to go traveling and doing a lot of stuff. And so I was really fortunate to go to a conference in Capri, Italy with my supervisor, Tac Mac. And this was one of these amazing experiences

42:52where I met people that I still know now, like Nav Shandell. And I met this one person, Jay Molino, who was a lab in Italy. And I was like, oh, I'm going to maybe hang out and go around a bit. And he said, I have a place in Capri. Why don't you go stay at my place? My dad's there and go stay there. And so me and this other postdoc stayed there. And it was just this kind of magical experience. I'd never growing up in Ottawa, Canada, I'd never seen lemons on trees. So that was just like this kind of

43:25amazing experience where it was like, this is a huge plus of academic research is you get to go to these different places and go see different people and experience different cultures and eat different food and different sites. So I think I always remember that one the most probably because it was one of the most early ones. And it really kind of opened me to say, wow, this is really cool. Definitely. So it sounds like this was perhaps the first big international conference experience. What was it like for you being at the conference?

43:57Scary. And you're like, you see people walk by that you've read all of their papers and signed out 100 times. A big thing was I was like a flower on the wall. And I think I tell this to a lot of trainees. That's totally OK. It's OK to exist in spaces where you don't know everybody. You're not even contributing to the conversation, but you're just there. And maybe something come up that you'll maybe talk to one person in this. So that was the case. I think it was one of the first experiences

44:27where I was like a fish out of water and you're just surrounded by all these superstars. But trying to be like, that's OK, keep your cool. And I try to tell people it's like it's not that I've gotten more comfortable over the years, but I've gotten more comfortable and uncomfortable situations. So existing in these spaces where, OK, you don't know everyone, new place, you're surrounded, you feel like imposter syndrome. Why should I be here and why shouldn't someone else be here?

44:59And that was a situation where I kind of had to try to dial those voices down a little bit and just push through. And lots of times just showing up is the most important thing. Just saying, OK, I'm going to do it. OK, I'll come with. Let's do it. I'm going to go to this conference. I'm going to go talk to this person. I'm going to meet this person. I'm going to shake someone's hand, look them in the eye. And I think that's a big part of networking in general is existing in these uncomfortable situations. And ultimately, through that, you're going to meet

45:29amazing people. And ultimately, these people are going to help you grow your life and career. Definitely. And just to build on that idea, I think there are so many amazing people in science. And unfortunately, that's not always how scientists are portrayed in the media, whether it's books, movies, or even when they're showing scientists on the news. I feel like there's a certain vibe that people have this expectation of what scientists are like. And so many people that I've met in science do not fit the stereotype. So we love talking about these quirky, fun, funny moments that scientists have just to show the human side of science that I think not everybody

46:02gets to see. So, Isaac, do you have a story or an example from your career experiences of a quirky lab tradition or just something funny or maybe a fond memory that you've shared with colleagues that captures this human side of science? I always think of the times, especially during my postdoc, the times I had with my colleagues were all scientists, were just all people. And one thing in Boston is it's really concentrated. There's a lot of different labs and a lot of different people. And so shortly in my career,

46:32I'd gone to a few conferences on cancer and especially metabolism of cancer. And I interacted with these different people and realized that a lot of them were in Boston. I had these colleagues. I had one in my lab, John Koloff. But then there was Sam McBrayer, Dana-Farber, Christian Dibble at Harvard School of Public Health, Brandon Nicolet at Lance General Hospital. And we were all kind of in Boston. So we said, hey, why don't we meet every month? Let's go for drinks and let's just talk science. And basically, we did this for several years. We would meet every month. We would go to this one

47:08dive bar, Lukowski's and Fenway. And we ended up going to another bar later. And we would talk to each other about science and challenge each other's ideas and push each other, I think, but also just hang out and talk. So these relationships that I developed during my postdoc, I've kept till today. I still talk to these people all the time. I talk to Brandon all the time, almost every week. And they've gone on to do amazing things. And so that was kind of like one thing we developed. It was just like,

47:39hey, let's just hang out, go for drinks every month. Let's keep it on our schedule. And we're able to support each other over the years as we went in different paths and different places. We're now all in different places. I think that's wonderful. I think kind of getting out of the lab and getting to know people is really important in science because you're building this community of, like you said, the network of the support system that's going to help you get through all these difficult transitions and challenges with the projects that you're working on. So I think that's wonderful. And I think having this community can help you tackle some of these big questions that

48:11you're working on. I mean, cancer research is rife with big unanswered questions. So if we took away the barriers that normally hold you back, Isaac, if you could have all of the funding staff technology and take away any feasibility challenges, what is the one research question that you would most want to answer? I wish I had a good answer. I think I want to pull apart core metabolic biochemical pathways. And I say I don't have a really good answer for that because it's such an open-ended question.

48:44And I think, again, going deeper is that questions are shaped over time as well. And they're shaped through experience and they're iterative. It's research. It's not search. Right. This isn't a rock hunt. Yeah. Yeah. So you keep looking and keep looking. So if I had all the funds in all the world, I think there's definitely new technologies, metabolomics, spatial metabolomics, spatial transcriptomics, different pharmacological screening approaches we do, genetic screening approaches.

49:15But all of this also comes down to saying, let's start with some pretty basic questions and let's see where it takes us. I think that's the big thing. And that's the excitement about research is that these really tricky questions, like this guy Doug Green calls it, they come from the eighth dimension because they don't just show up. They come from a lot of reading. I stand on the shoulder of giants and other people doing other research. So I think if I had all the funding, it would be to continue to ask very basic questions surrounding biochemistry and metabolism and seeing

49:52how we can scratch the surface and uncover these different basic pathways. And then how can we bring this all the way from the bench to the bedside? How can we go through the steps of, and this is where it also really changes is having the funding to do the in vivo studies. So the animal studies, this is very difficult. It requires a lot of time. And then to translate that into new therapies and ultimately clinical trials. It's not that I would ask different questions and I hope to have as much

50:24funding as possible. I'll never limit it on questions, but it's to continue to ask these questions, continue to have a lab and continue to train people. And then it's also to really continue to see this go from beginning to end and to see this translate from very basic questions ultimately into therapies for patients. Well, Isaac, I think you brought up so many important points in your response. And I think for listeners out there who may be on the scientific path themselves, it can be helpful to hear from people who've walked it before them. And I think sharing advice can be

50:56tremendously valuable. So when you look back on your own career path, is there a piece of advice or something that somebody told you that really helped you get to where you are today? Probably comes from my dad. He would always say, if it was easy, everyone would do it. That stuck with me in terms of saying science is art. And especially I think science is and it should be accessible to everyone and open opportunities and provide support. But a big thing also for people coming into science is to realize that it's hard. It's a lot of failures. It's a lot of grinding.

51:31It's a lot of monotonous, non-exciting work. But you have the opportunity to ultimately make discoveries that last forever. So some of these things aren't easy. They are hard. But if you're able to do it, you can potentially change everything. And so that's, I think, some of the advice that I've been given and have continued to stick with me throughout my career. Definitely. It's worth the grind, I think. It's worth the grind. Yeah. You just got to like, have you heard of Marshawn Lynch? So he's a former running back to the NFL. And he had this really amazing run where everyone tried

52:08tackling him and he just kept running and he got to the end zone. And he was interviewed by 60 Minutes. And he's like, if you just keep going, eventually you're going to get there. If you keep pushing and if you face your challenges head on, if you keep going and going and going and going, you're going to get there. You're going to get to the end zone. And then the person said, is there a bigger message in this? And I have this quote on my wall. I don't want to swear because he swore, but he said,

52:40run through a mother effer's face. You do that, then you don't have to worry about them anymore. So he was kind of saying like, you're going to have people coming at you, trying to tackle you. You can decide to run away from it. You can try to decide to run around it, or you can decide to run through it. And if you decide to run through it, yeah, you're going to get hit and it's going to be hard. But ultimately, if you run through these problems and challenges, you can overcome them. And this is the most direct path towards success.

53:11I like that. Yeah, I think dodging the problems, they have a potential to bite you later. Yeah, exactly. Exactly, exactly. Well, Isaac, this is fantastic advice. Is there any other last piece of advice or last note of inspiration that you want to leave all of our listeners with today? For those listeners in science, understand that it's an up and down pursuit, that projects go up and down. We have no control over the results. We can ask really good questions. But we don't know if it's going to support our hypothesis or not. Are these experiments?

53:44So to also build a network, I think for people in science to understand that we can't be an island. We have to have support within the lab, within the department, within the institute. And then outside of that, I have so many close colleagues that I've met through conferences that I've kept in touch and have really helped me throughout the years. And so that's a big thing for people in science, especially newer people in science, is to understand, okay, it's really hard, but we can get there. And especially with the support of others and learning from others and facing failures and overcoming rejections, we can get there.

54:19And ultimately, we have a very unique opportunity to make discoveries that could ultimately help people. I've always felt very privileged in this position and very lucky that I get to show up and do really cool stuff that could ultimately help someone. Well, wonderful note to end on, Isaac. I appreciate you sharing all of these insights with us today. If our listeners are curious and they want to learn more about you and your work, what is the best way for them to get more information? So we have a website, harrislab.org. As was mentioned, I'm going to be moving to McMaster

54:52University. I believe my website is up or will be up. I'm also on Google Scholar. I'm on Blue Sky, not on Twitter, but definitely reach out. I'm always open to talk and reach out to the people in science that you identify with that connect to you. And everyone's willing to chat. Everyone's willing to chat about the research and to help you along the way. Outstanding. Well, listeners, definitely check out Isaac's website, Get Connected. And Isaac, thank you so much for taking the time to speak with me today and to share some of your story.

55:22Thank you for having me on here. This is really, really fun. It's been such a pleasure to chat with you. And listeners, always wonderful to have you here with us as well. We hope you'll join us again next time for another episode of People Behind the Science.

55:40People Behind the Science