Alicia: Today we’ll meet Kip Guy, Dean of the College of Pharmacy. He is identifying and developing new drugs for neglected diseases using chemistry.
Kip Guy: Like most people, I like neat solutions to problems. So when I started out, it was very attractive among the science fields because you could explain with theory most things. And then as I grew and became an older chemist, I realized that like most places those explanations weren’t nearly as black and white as we thought, but that was part of what got me started there. And I really like to do things with my hands and things that are practical, so math and physics lost me for those reasons and I stuck at chemistry.
Alicia: So let’s talk a little about your recent publication in nature chemical biology. What’s the impact of your research to block cancer causing proteins in the cellular level?
Kip Guy: So we were working on a system that cells use to get rid of old proteins. If you don’t get rid of the garbage just like in your house, things get really messy. So there’s an elaborate control mechanism for doing this in cells and it goes on every day in every cell. One of the things that goes wrong in cancer is often problems in its pathway, and those can manifest with proteins that should be gone hanging around and continuing to drive the cells into do things like grow and divide. So as a control mechanism, it’s been of interest for a long time. There were drugs available that would really shut down the whole process and those were toxic, because they affect all cells. So we were interested in whether or not we could be more specific in controlling that process. So we targeted the proteins that were important for regulating just a small portion of that protein homeostasis it’s called. So we thought what was going to happen was when we would get a compound which would affect cancer cells that had a defect in that particular part of the pathway, and they would do the same thing as the big hammer. They would kill those cells, but they would leave alone all the other cells. We got a really nice compound that does exactly what we want in the control mechanism. It has all the effects we wanted on cells, except they don’t die. Alright, so we stepped back for a minute. “Is this not doing what we think? Does it not work the way we think?” Everything we looked at it was normal. We figured out relatively quickly that while we didn’t kill the cells, we prevented them from being metastatic. So they couldn’t grow outside the context of a tissue. So our very specific compound in this very general process had a very specific effect against cancers. It just wasn’t the one we were expecting. And so now, we’re in the process of actually understanding why does that work that way? How does that affect other types of cancers?”
You know a lot of cancers it’s not the primary region that kills you, it’s often the metastatic regions. And so being able to block that, if we can do that in a way that’s really effective and safe, that could be a game changer in a lot of tumors. Lung is probably one of those. So you know, it’s a really exciting thing and people have talked about doing this for a long time. We’ve had some compounds that would do it sort of and we’ve had some biologics that would do it. You know now whether or not we’re going to be able to convert that into a drug that’s usable in the clinic, that’s a long road to go down but it’s an exciting road to be on.
Alicia: Thinking overall, what have been some of the most fulfilling moments related to your discoveries in the lab?
Kip Guy: It’s when you break your own model and you really learn something fundamentally new. That happens in a lot of different ways. As a teaching example, we were working on a drug for malaria (which is a major killer of children) and we had a model about how to pick which drug to take into preclinical studies, and that model kept telling us this drug was going to disappear in the body in 15 minutes. So we kept on working and we tried something else. We could never get that better. So in frustration, we went ahead and we said, “Alright, we’ll try one mass experiment before we stop” and it had a half-life of a week in a mouse. Didn’t mean it was going to do that in a person, but it did change the whole game. And so, it really pivoted the way we thought about doing that part of our science completely. I mean it stuck with me in a way that every student I have now gets that story usually the first week in the lab without too much eye rolling.
Alicia: So speaking of students, how has what you’ve learned through your research impacted the way you train students?
Kip Guy: So obviously as an academic, that’s a major part of what I do. Most of my students go into industry and do drug discovery in that setting, and I think the aggregation of my scientific experience has been it’s never as simple as you think it’s going to be. And you really need to bring a wide range of thinking, meaning to construct different models, different ways of explaining what’s going on, and try to break them. And you need to bring a lot of disciplines to the problem. One view point, one approach, is usually not going to work. It’s only when you bring them all together that you have a reasonable probability of actually making it through toward something that approximates the truth. So I train all of my people that way from day one and it’s a big shift for me. I grew up in an environment where you do one thing and you do it really, really well. So this has been a shift that’s happened right throughout science and throughout medical discovery in the last two decades, and we’re still adjusting as a culture to working that way, but it has really impacted how I train students. The other thing I would say is I noticed people got stuck on simple things very often. So they were doing one experiment after another, but they hadn’t thought about what comes after that experiment. So maybe we weren’t doing the best experiment. I spend a lot of time now working with people on how to plan, how to think through the problem, think through all the things that are going to go wrong, be able to adapt to that quickly rather than getting thrown by it. It hurts if your expectation is it’s going to work. I think you have to approach it with the idea that I’m going to do everything to stack the deck in my favor. Most of the time it’s not going to work. When it does work, I’m happy.
Alicia: So what motivated you to move into the administrative area of this academic science?
Kip Guy: I currently have a drug in clinical trials for malaria, so that’s 12 years of work and the team has members on every continent. You know I realized I was pretty good at organizing people and work and motivating people towards common goals, and probably even more importantly, motivating them towards finding those goals, things they could agree on they wanted to do. And I realized I was getting much more interested in how we implement the output of the science in addition to actually doing the science myself. So I started looking for opportunities where I could have a bigger influence on that side, on picking the problems that people focused on as a group, on really trying to make those practically relevant, especially to the things I care about which are big health disparities and underserved populations. I realized one of the other really big impacts we have is teaching. And so, I wanted to be in a place where I could help to combine the way we think about research (that interdisciplinary inter-professional approach) with the way we teach in not only research, but the way we teach clinical practice. I see those all as a big functional working group that’s pushing toward something in common, rather than separate smaller groups working in disparate areas. So that motivated me pretty hard to start looking at dean positions and for somebody of my background, pharmacy is the most sensible place, right? I work on drugs. That’s what ties all of pharmacy together.
Alicia: So why did you choose to come to UK and what has inspired you about this place now that you’ve been here for a little while?
Kip Guy: The first thing I’d say is why wouldn’t you come here? It’s an incredible place. It’s got an amazing faculty. A long, rich and successful history of positively affecting clinical practice and positively affecting the research world. It’s one of the strongest colleges in the country. It’s one of the strongest colleges in the world. It’s hard not to be attracted here. In addition, for me, it’s smack in the middle of an area where we have really high health disparities, some of the worst in the U.S. I can work the way I want to work with the kinds of people who are here, the amazing faculty we’ve got in the college and focus on problems that are really serving unmet needs. It’s for me a perfect storm.
Alicia: So you mentioned the health disparities, and one of the things that we’re talking about a lot nationally is opioid abuse. Obviously, part of that is a pharmacy issue. What is the College of Pharmacy here doing and what can it bring to that public health challenge?
Kip Guy: We have a pretty heavy emphasis on substance abuse in general and opioids is part of that. So we’ve had faculty involved in policy and outcome studies. So people like Jeff Talbert, Patricia Freeman, who’ve done a lot of work in that area understanding what’s really going on, understanding how the drugs are used, where the problems arise, and what interventions work. And a number of our faculty have also carried that outcomes work forward to the next step. And so, people like Patricia Freeman, Dan Wermeling, have been intimately involved in changing the law in the Commonwealth to enable dispensing of opioid antagonists like naloxone that can overcome an overdose. And getting those really out into the community and usable right where they’re needed when an addict actually goes into overdose. They’re actively out training pharmacists about how to do that, actively out working with public health departments in order to make sure those drugs are in the right hands, and still campaigning in order to make sure that we’re going to have access everywhere that we need them. We also see that as an opportunity for more basic and focused clinical work. So there’s a lot of interest in the college in building strength in those areas in order to be able to deliver better therapeutic interventions or using interventions that we’ve got in ways that we’re not right now that would be more effective.
Alicia: What are some of your top goals as Dean of the College?
Kip Guy: There are three major ones. We have a long history of really innovative education here and I want to make sure that we continue to grow and innovate both in teaching pharmacy practice, and also in teaching pharmaceutical sciences and research. I want to make sure that as a college, we engage in inter-professional and interdisciplinary research, especially in the areas where they are going to serve under-met needs. And then I want to make sure that we continue to have a broadly inclusive and service oriented culture. We’re not just about working in the lab or the clinic. We’re also about living in this community and doing well by it.
Alicia: My last question for you is, what would you tell someone who’s thinking about joining the research enterprise here at UK?
Kip Guy: Come right now. It’s a great place to do research. It’s a great place to learn it. You’ll have an immediate effect and you’ll be able to grow into being the best scientist you can be.
