VO: Today we’ll meet Allan Butterfield. He is a Professor of Biological Chemistry in the College of Arts & Sciences at the University of Kentucky. He also serves as Associate Vice President for Centers & Institutes within UK Research. We’ll look back at his 45 years at UK, but first he shares when he knew he wanted to pursue chemistry.

[00:01:03.66] ALLAN BUTTERFIELD: So it was actually quite early. I knew I was going to be a chemist in the seventh grade, although I didn't know exactly what a chemist did. I only had, in the small town of 500 people in Maine that I grew up in, a pharmacist in the next town, and I associated pharmacy and chemistry. Well only later did I realize pharmacy is kind of like applied chemistry. So if we had a chemistry degree so much the better.

[00:01:33.00] So when I went to undergraduate school at the University of Maine, I had an opportunity when I was a junior to be picked out by my professor and asked to do research for an NSF-sponsored project. And for the first time in my life I could see the great joy of discovering nature's secrets. And so I was kind of like a detective, and that kind of turned me on about research. So that's how I got into it.

[00:02:04.11] My first graduate studies research project, which was taken at Duke University-- and I know for UK people that's an issue, but nevertheless, that's where I was, and I did my postdoc in the Duke Medical schools. In any case, my first graduate project was on understanding the electron movement of a protein called cytochrome c. And in mitochondria, which provides our energy for all of our cells, this protein is key for ultimately making what we call the currency of the cell, ATP. So I figured out a good experiment on my own, solved it, and sure enough, it led to a secret being revealed. And so I thought, well, now I'm on my way.

[00:03:02.42] And later on I did more neurological kinds of projects as part of my dissertation, and that led into a whole new area of science for me, which was neuroscience and neurochemistry, which I didn't know anything about. But that's why you go to graduate school and postdoc, to learn. And, my gosh, it's just fascinating, just to think about how the brain works. And it turns out that if you know the chemical principles, you can actually explain how does something as complicated as the brain work.

[00:05:03.62] ALICIA: So, if you had to sum up your signature research discovery, how would you do that?

[00:05:10.91] ALLAN BUTTERFIELD: If you don't mind just a brief story about that, I am fascinated by Alzheimer's disease, and that's what I do for research for the most part, along with Down syndrome and chemo brain, as the patients call it.

[00:05:28.34] But in the case of Alzheimer's disease, walking back from Sanders-Brown Center on Aging to the chemistry building-- two or three blocks-- I kept asking myself, why are there so many proteins that are known to be altered in Alzheimer's disease, or lipids, part of the cell membrane. Why? Why isn't there just one, like sickle cell disease? Why isn't there just one? And it occurred to me. I said, oh, what if there is a free radical in the brain that is hitting all these different proteins and different lipids and causing them to be defective?

[00:06:06.77] So I immediately turned around, went back to Sanders-Brown, borrowed some of this peptide that accumulates in the brains of Alzheimer's people called amyloid beta peptide, or Abeta, and I put it in the appropriate instrumentation. And sure enough, up comes a signal showing a free radical was there. And I said, whoa, this is fantastic.

[00:06:35.09] And I had this brilliant graduate student from Ashland, Kentucky, who was very ambitious and who was brand new. I said, this is your dissertation, right here. So I outlined for him the big picture, and he filled in all the details in 25 papers in three years. Isn't that amazing? He's very ambitious. He's now a full professor at a medical school in Arkansas.

[00:07:00.98] So our lab discovered the free radical associated with this peptide and changed the paradigm of how you think about the pathogenesis of Alzheimer's disease. Free radical oxidative damage has to be part of the paradigm. And I think it's widely accepted.

[00:07:22.34] ALICIA: How long ago was that?

[00:07:24.44] ALLAN BUTTERFIELD: 1994. Published in Proceedings of the National Academy of Sciences, a pretty good journal. And not initially accepted, as often, when you shift the paradigm, it's very difficult. And the next year at this big, giant, scientific meeting that happened one year after I presented this research at that same meeting, so one year later, the same people who were skeptical said, oh, yeah, we knew Butterfield was right all along. We reproduced his work, and it's fine.

[00:07:59.14] So that, of course, is very satisfying. It's a little bit risky when your neck is stuck out that far. But, frankly, really important research only happens with a little bit of risk-taking and pushing the envelope

[00:08:24.26] ALICIA: So it seems like serendipity, in terms of you thinking, what if I look for this free radical?

[00:08:30.55] ALLAN BUTTERFIELD: Yes. But that's how creativity works. I was nice and quiet, just walking along Rose Street. In fact, so deep in thought about it that I almost got hit by a car. But then I thought, oh, there's something here. There's just got to be something here. Let me test it. And sure enough, it was there.

[00:08:53.00] And then we explored that and found-- we were the first to use a technique called redox proteomics-- we identified which brain proteins had been hit by this free radical, or free radical reaction products, actually. And, sure enough, they fit the paradigm of Alzheimer's disease, the symptoms, the pathology, and the biochemical alterations very, very well.

[00:09:21.32] So we published the model in 1994, and we've been funded on this work since. And the NIH is asking us, try to disprove your findings, or your hypothesis, and your model. We developed a model to explain Alzheimer's disease. And they want us to try to disprove it, which is good science, right? And I tried my best, but so far it's holding up pretty well. And as I said it's been replicated by many people, so that makes us feel good.

[00:09:58.74] ALICIA: So is this finding related to the amyloid discussion? We're targeting all of these drugs with amyloid. There have been so many failures. Does your work play a role in that?

[00:10:13.20] ALLAN BUTTERFIELD: It certainly does. And that's mostly because most of the people who work on this don't remember the chemistry they had to learn in order to become scientists and physicians.

[00:10:25.40] Look, chemistry is nothing if it's not an equilibrium science. So what's happening is that most of the drugs are targeted at the end product of amyloid beta peptide, aggregating as this big giant meshwork. This is all intermingled sorts of things, like a bowl of spaghetti. Something like that.

[00:10:52.92] And, well, that is the problem. That's outside the neurons. But that starts with little oligomers, dimers, or tetramers, something like that. They are very hydrophobic amyloid beta peptides. It doesn't like water, so it goes right into the membrane. And that's where the free radical process starts, right there. And it oxidizes the lipids, and that makes very toxic products that then attack the proteins, and make them dysfunctional, and they don't work.

[00:11:38.67] So the targeting, then, needs to be way early, at the point of oligomers, not at the point of plaques. Now it is true that plaques themselves are damaging, but way downstream from the original process of the oxidative damage.

[00:12:00.15] ALICIA: So they're looking at the wrong point in the process.

[00:12:01.92] ALLAN BUTTERFIELD: Looking at the wrong point, not checking, sometimes, when the antioxidants have not worked out well. As a scientist, you have to be open to-- maybe, your ideas need to be modified somehow. But the truth is is that these studies often are not conducted in a way to test the underlying redox status of the patients treated. So, already, if they are pretty reduced, if they have a low oxidation state, then adding more antioxidants not going to do anything, right? That's just one case. Maybe you have to look at the right kind of antioxidants to be able to do things. So we are certainly working on that.

[00:12:51.21] Now what we have made is a new discovery that we published in 2019 in Nature Reviews of Neuroscience, a pretty good journal. It is a summary of all the oxidized proteins involved in metabolizing glucose, which is the main energy source for the brain. And we discovered many proteins within the process called glycolysis that are oxidatively dysfunctional.

[00:13:25.26] Moreover, when glycolysis is finished, there's another cycle called the TCA cycle, and part of that also doesn't work because of this oxidative event. And then there is the electron transport chain, which I had mentioned earlier about cytochrome c, sort of coming right back to the early days. And the big, giant complex that makes ATP, called ATP synthase, is itself damaged, and it doesn't do that very well. So we knew already-- people who had done PET scanning had shown glucose was not used very well in Alzheimer's brain.

[00:14:09.79] By the way, these findings also apply to the early form of Alzheimer's, called mild cognitive impairment, way, way before dementia, way before dementia. But you still see these changes of oxidative damage. It's pretty interesting.

[00:14:25.62] Anyway, our model says, there's not enough ATP because of oxidative damage to all these enzymes. So if there's not enough ATP, calcium, which is on the outside of a neuron, all of a sudden calcium comes into the neuron, a lot of it, and that kills the neuron, basically.

[00:14:56.08] So a recent paper studying tens of thousands of patients from three continents, by different imaging modalities, one to look for Abeta deposition, one to look for glucose metabolism, and one to look, by MRI, at the thinning of the hippocampus, that part of the brain is used for memory formation, and the frontal cortex, right here in your forehead, that is used for executive thinking, reasoning, figuring out tasks, how to do things, the very things that are lost in people who have Alzheimer's disease.

[00:15:43.32] Now, what they discovered in people who have inherited Alzheimer's disease, 22 years before the symptoms appeared, they asked a question: Which of these three things happens first? Answer, deposition of Abeta. That means the plaques, they can detect. Meaning, as I explained earlier, the oligomers were there. And so they've been in the neuron, killing the neurons.

[00:16:15.95] Now, you wait some years, what's the next thing that shows up? Glucose dysmetabolism. The very thing we had found and proposed. And lastly, because the calcium had come in because of that and killed the neurons, the neurons have died and the hippocampus shrinks and becomes thinner, as does the frontal cortex. And the MRI can pick that up.

[00:16:42.26] So I'm thinking, wow, this is an imaging method out of real patients, that has confirmed all of the work we've done with patients.

[00:16:51.74] And I must say, none of this could have been done, not any of it, not only because of I needed the NIH funding, which I've been lucky enough to get, but because of what we have here at UK that is so unique. One, we have a world class aging center, the Sanders-Brown Center on Aging. And when I came to UK from Duke, I was met two weeks later by Bill Marksbury, the founder of this institute, and we became instant friends. I mean, immediately. And we were friends right until the day he passed away. It was a great loss for UK.

[00:17:39.02] Anyway, he allowed me, a chemist, to have access to the brains, because he knew I was a neurochemist. And he allowed me to have human brain tissue to study our hypotheses, and that has really made a great difference. Now, in that process, it illustrates the other great advantage at UK, and that is, there's a whole ethos of collaboration. That is a tremendous advantage to our university.

[00:18:14.54] Being at Duke, for example, there are a lot of silos, they're all members of National Academy, and there's a, why do I need to talk to you, that sort of thing. Now I'm sure that's better than when I was there, but nevertheless, it does illustrate that. I had a colleague at Harvard who was a subcontractee of one of my NIH grants. And when I went to visit him he was just so sad, because he felt he could never talk about his research with anybody there for fear it would be stolen. Isn't that awful? And here, I present my specific aims to people and ask them to criticize them. And how much better to have that be done by friends, than by the study sections, and the people who actually evaluate your proposal. So I'm pretty happy about that.

[00:19:09.53] Anyway, great advantages of being at UK. I am so fortunate that I've been here, now, 45 years.

[00:19:17.47] ALICIA: Wow. And over that time, you've been heavily invested in mentoring students. Tell me a little bit about how your research over the years has impacted the way you train them and how you perceive your responsibility to train them.

[00:19:35.57] ALLAN BUTTERFIELD: Both are great questions. I'm still a 1968 liberal hippie in my mind, and I cheer for the underdog. I just do. What really motivates me is having grown up poor myself, and knowing what disadvantage means, in terms of opportunities.

[00:20:05.39] I have a great affection for people from Appalachia, for example. The mountain that's the last of the Appalachian Mountains in the United States is, like, 20 miles from where I grew up. So I sort of have a characteristic not so different than a lot of people from Appalachia. And what those folks have every time I see them in my lab are bright, bright people, and have a tremendous work ethic, and they're willing to work really hard. They just need to get a little bit of encouragement.

[00:20:44.80] I have three things that I tell all of my students. When they come to work with me, if they want to work with me, I say to them, you got it, are you smart? If you're really smart, this is a good place for you. If you're just average, it's not. Are you a hardworking person? Because I am, and that's the only kind of people I want around me. And they say, yeah, I am, I grew up working hard. I know that's like. And I say, are you a nice person, can you get along with people, can you work in a group, because I have no room for prima donnas. None. We are a collaborative lab.

[00:21:27.41] And I'm just shy of 700 papers published, so we've been pretty productive, I would say, over the years. And that's because of the great talent that has always come into my laboratory.

[00:21:57.55] The only ones who come to talk to me are already so self-motivated, and so disciplined, and so focused, I don't have to make them do anything. I just give them the image and the vision of what the picture looks like and ask them to go solve the problem. And they're so bright, that they do it. That's the thing.

[00:22:19.22] So mentoring is providing the resources, the support, for these students, and encouragement in a, let me emphasize, safe environment, because I have deliberately trained a lot of people from Appalachia, people of color, and a lot of women. All three groups are highly underrepresented in the faculty ranks in the discipline of chemistry. And I want to see, relating back to my earlier remarks of what I still have in my head, is helping the underdog. All three groups are underrepresented in chemistry, and I want to see them succeed and become faculty members. So I have encouraged such people to come into my group.

[00:23:16.64] But I have extraordinarily high expectations of all of the students. I just do. In the United States, the average number of papers published from a chemistry dissertation is three, and I always told my students, you can't graduate from me unless you have six, minimum, could be more. It's got to be six, in good journals, really good journals, and in the same four- or five-year time period. Well, no big deal for somebody who's really a hard-working person, which all of these students have been. I have been really blessed with that.

[00:23:52.58] I also have train a bit over 170 undergraduates in the lab, and 60 or 70 of those have published papers from their undergraduate research, which it's quite an accomplishment when they're taking 16 or 18 hours of credits a semester. Again, very bright, very hard working. I've been very fortunate.

[00:24:17.69] And then I've had about 30 postdocs and visiting scientists. I've developed a wonderful relationship with the University of Rome – unfortunately, closed now, because of the virus over there – but those folks all trained with me, and now are professors at the University of Rome in biochemistry. Again, really hard working, very bright, all very nice, and most of them female, but a couple of males in that group. They are fabulous, and we maintain collaboration, even now.

[00:26:43.65] ALLAN BUTTERFIELD: Not everybody is compulsive like me and knows at seventh grade what they're going to do. And here's the thing, all through my life I've been so fortunate to have good mentors, too. That's partly how I learned that, and part of paying it forward, really. I mean, I wouldn't be where I am without very important critical check points in my life that you look back on and say, boy, if you'd gone the other direction, you'd never be here doing this, ever. So this is pretty amazing.

[00:27:27.52] I'm so grateful for the opportunity to have been a professor here for all these years, and I look forward to continuing it. I have four NIH grants, and I'm not ready to retire yet, and thank God I'm healthy so far. I hope to be. And it's a great privilege to be here, I must say. I'm so glad that I came to UK when I was recruited.

[00:31:56.80] ALICIA: So you've moved into more administrative roles in addition to all the laboratory science, which you are continuing to do. Why did you choose to do that?

[00:28:42.55] ALLAN BUTTERFIELD: Why have I gone into administration? Partly, it is because the vice president asked me to. And when I looked at her, a full-time vice president at 50% effort, and the other 50% is a fully funded NIH laboratory, I was pretty impressed. Those are the kind of people I want to associate with. And she asked me to handle centers and institutes, and then recently, the university has identified six research priority areas, and she's asked me to be in charge of that as well. So it's a lot of work, to say the least.

[00:29:59.10] The point is that administration allows me to share my view of where research goes, now, with a lot of input from faculty, I don't just dictate this, and also I enjoy working closely with the other associate VPRs and also working with Professor Cassis. She's something else to admire. I would say, just, highly, highly successful.

[00:30:32.55] Now, the downside is that the work on science research hasn't slowed down a bit. Well, there are only 24 hours a day my goodness, last night, I had eight hours of sleep, and that's the first time I've done that in about three months. So that is a downside. It's a busy life. My wife of, now, 51 years has sort of gotten used to me, by now, and knows that I'm really dedicated to the work.

[00:31:13.52] And, especially, trying to solve this horrible, horrible disease, Alzheimer's disease. I don't expect to solve it personally, but if I can contribute to a better understanding and identify key specific targets that might be useful, I think I will have done something good for humankind, and I'll be proud of what I've been doing. I am proud of what we've been doing.