Episode 61: Dr. Lance Wells on Glycobiology

Introduction to Episode

0:00Hi, you're listening to Let's Talk Chemistry, a podcast by Chemtalk. On today's episode, we interview Dr. Lance Wells, Professor of Biochemistry and Molecular Biology at the University of Georgia and Associate Director of the Complex Carbohydrate Research Center. Dr. Wells researches how dysregulation of glycosylation can contribute to disease, as well as how glycans can be used to develop more effective treatments. He also shares how working with families affected by these diseases have shaped his research,

0:34inspiring him to focus on real-world translational impact. We hope you enjoy!

0:40Hi, and welcome to another episode of Let's Talk Chemistry. My name is Jasmine. My name is Dia.

Dr Wells Background

0:48And my name is Erin. Today, we are sharing with you the story of Dr. Lance Wells, a professor of biochemistry and molecular biology at the University of Georgia, who also happens to be my research mentor. He also serves as the president of the annual Society for Glycobiology, leads a research lab, and is the associate director of the Complex Carbohydrate Research Center, or the CCRC. His college education began as an undergraduate at Georgia Tech in Chemistry, where he worked for a couple years in a lab and really enjoyed bench work.

1:21This led him to pursue a PhD in biochemistry and molecular biology at Emory University. During his PhD, Dr. Wells conducted a postdoc at Johns Hopkins School of Medicine, and this provided the necessary medical background for the research he does today at the CCRC. The CCRC is made up of 16 to 17 labs completely dedicated to the study of carbohydrates, and his lab has a human disease focus.

Carbohydrates in Life

1:49There's four major biomolecules of life. I think most people know the DNA, RNA protein, right? So the nucleic acids and proteins, that's two of the four molecules of life. But the other two that are essential for life are lipids or fats and our carbohydrates. Carbohydrates, now when we say carbohydrate, I think most people think, you know, things to avoid eating and, you know, sugar, things that make things sweet. And what we're talking about is large polymers, sometimes small polymers, but they're attached

2:22to either lipids or they can be attached to proteins, most commonly is what my lab studies, or they can even be attached to nucleic acids, we know now. They can actually be attached to the other three molecules and they affect function, and they can work independently. And so, like on the second floor here, I'm up on the third floor, where we're all animal, we all work on some type of animal or human disease. On the second floor are the plant people, and they're studying the plant cell wall, right, which is heavily, has a lot of polymer in it. Glycobiology used to be an underappreciated field, but in recent years, it has garnered

2:56much more attention, thanks to the efforts from scientists like Dr. Wells and institutions like the CCRC that are spearheading this initiative. So, how did it all begin? Well, Dr. Wells started out at the CCRC researching a small glycan modification called OGLICNAC, which stands for O-linked beta-n-acetylglucosamine. This may sound complicated, but really, it's just a sugar. Or beta-n-acetylglucosamine, or GLICNAC, attached to a protein via an oxygen atom, specifically

3:30on the amino acids serine or threonine. Together, the glycan and protein are referred to as a glycoprotein. That makes a lot of sense. But what makes OGLICNAC so special? I wonder what drew Dr. Wells to study this particular modification. Great question, Dia. That leads us perfectly into hearing Dr. Wells share what sparked his scientific curiosity about OGLICNAC, and why it has become such a key focus of his research.

Dr Wells Research

3:59When I first set up my lab, I was working on a really small modification called OGLICNAC. So, it's just a single sugar that gets added to nuclear and cytosolic proteins. So, usually when you think glycoproteins, you think proteins that are going to go through the secretory pathway and either end up on the plasma membrane or be secreted from cells. But it turns out, and that's where we thought all sugars were up until the mid-1980s in terms of glycoproteins. But then Jerry Hart, who's where I went and did my postdoc, his lab had discovered that

4:29there was sugar on, just a single sugar on nuclear and cytosolic proteins. And so, my lab's studied that for many years. What really kind of bumped that research up in our lab in the last 10 years was about 10 years ago now, we had a geneticist reach out to us who had a family with three affected males with intellectual disability, and they all had a mutation in the enzyme that puts that sugar on. It's called OGT. And so, we got really interested in that, obviously, because this is an enzyme we'd been

5:01studying for a long time. We started with one family that we characterized biochemically and published. The latest is about 75 families now with mutations in OGT, and so it's an intellectual disability syndrome. And we're actually, two weeks from tomorrow, November 9th, we're having the first annual OGT X-length ID meeting. And that's going to have physicians, scientists, but also families, affected individuals getting us all together and trying to figure out, you know, what can we do? How can we help move the field forward?

5:32Wow, it's incredible how Dr. Wells' research is driven by real patients who could benefit from his lab's discoveries. That kind of direct impact must be so motivating. Absolutely. And what's even more impressive is the sheer breadth of research happening in Dr. Wells' lab. Beyond their work on Oak Lick-NAC and its role in XLIDs, they're also investigating congenital muscular dystrophy and many other diseases with the power of mass spectrometry. A lot of my lab studies congenital muscular dystrophy.

6:05And so congenital muscular dystrophy, unlike, say, like Duchenne's muscular dystrophy, which is the most common form, congenital muscular dystrophy is actually due to defects in the proper glycosylation of a single protein called alpha-distroglycan. And so my laboratory has been working out that pathway for the last, my lab and many other labs around the world, they've been working out that pathway for the last 10 or 15 years to try to figure out what are the enzymes involved, what are the gene defects that lead to disease, and why do they lead to disease. And so that's a lot of what my lab does.

6:35The other part of my lab is a mass spec lab, right? So we do a lot of mass spectrometry, kind of cutting edge mass spectrometry. We've looked at things like the SARS-CoV-2 spike protein and its glycosylation, and whether it was going to have kind of holes in the glycosyld, if you will, so that we can make antibodies, which of course it did. And that's why we have vaccines, because it does have holes in its shield. Thank goodness, because not all viruses have really big shield openings. Hearing from Dr. Wells reminds me yet again just how important it is to understand glycobiology.

7:08You could say it's a pretty sweet science. Indeed it is. And guess what? It turns out, glycans aren't just the cause of many diseases. They can work in designing better drugs to treat them, too. Here's Dr. Wells on glycans and therapeutics. So in the treatment, right, therapeutics, it used to be almost all therapeutics were small molecules, right? Aspirin, Tylenol, or whatever, antibiotics, right? But now they're biologics, right? So there are things like Herceptin and, right, these large proteins that we're using in therapeutics.

7:42But those are glycoproteins, right? And so whether it's heparin that is used in every surgery on the planet, which is a big glycan molecule, or whether it's any of these monoclonal antibody therapies, all monoclonal antibodies are modified by glycans. And the glycans affect not just, you know, they affect the way they behave in terms of their half-life, how long they stick around, their effector function, you know, do they target ADCC, which is what sometimes you want, sometimes that's not what you want.

8:13And you can tune the glycosylation to make the antibodies do what you want them to do by changing the glycosylation on them. Yeah. And I mean, even something like EPO, right, which is given to cancer patients when they're taking chemo, right, to keep their red blood cell counts up, right? EPO is a glycoprotein, and it's actually a protein that we engineered to have more glycosylation on it because it improved the half-life of the drug. And so where the patient didn't have to come in every two days and get it, they could do it like once a week, right?

8:43That, you know, things like that have helped. EPO is also, that changing it from three sites to five sites is also how they test people for EPO in the Olympics and things like that when people drug dope, right? So the people use EPO to increase their red blood cell counts, like bike riders, like bicyclists, and we can catch them because the EPO that's on the market, your natural has three in-link glycosylation sites, but the stuff on the market has five, and that's actually how they catch them. That's what they're screening for.

9:13Lycosylation really does play a role everywhere in therapeutics, from anticoagulants to cancer treatment. I guess Mary Poppins was right to say a spoonful of sugar makes the medicine go down, or rather, a well-placed glycan can modify drugs to be more effective. Yes, Erin, with that sort of insight, Mary Poppins could have been a glycobiologist in disguise. Maybe next she'll sing to us about glycans and biofuels and remediation. The possibilities are truly endless.

9:44The collaboration that Dr. Wells is involved in doesn't just end with the CCRC. Let's hear from him sharing his experience working with the thought leaders in the field. I had the good luck that I was the person that the original geneticist reached out to with the OGT-X-linked ID. I mean, he could have reached out to half a dozen other people in the field easily. And then we followed up on it, right? And we decided to really work on it and put a couple people on it. And that's been really rewarding. I really appreciate working with families. Obviously, I'm not a clinician. I can't give medical advice.

10:15There's nothing quite as motivating as seeing a sick child, right? So it can really motivate you and your lab to, you know, like, oh, maybe we ought to work a little harder or a little faster, right? So to try to help, you know, put something in the hands of people that are doing translational research, right? Because basic research leads to translational research, right? The whole idea is what we do in the bench. How do we get it to the bedside eventually, right? And that requires a lot of people. In terms of the glycobiology community... The field of glycobiology seems to be expanding at an exponential rate.

10:49With new discoveries being made on the daily, it's so exciting to imagine how much more progress lies ahead. Here's Dr. Wells reflecting on some of the remarkable advancements he has witnessed and contributed to over the past 20 years at the CCRC. In the last 20 years, so many things have changed in terms of what we know scientifically. The tools have changed, right? CRISPR-Cas technology, gene editing, actually being able to really think about the potential for doing gene therapy for certain diseases, right?

11:21That was just off the table 20 years ago, for the most part. In terms of Athens and the University of Georgia, I mean, I think we've benefited from having some amazing, probably underappreciated people in the upper administration. I mean, I think David Lee, when he was vice president for research, changed this university. He really brought it up. I mean, it was already a research one university, but he took it to the next level. And that's been augmented now by Jack Hugh, as serving as the provost, really pushing that. I think those are huge, huge things that have happened.

11:55Obviously, the CCRC, 20 years ago, the animal part was much smaller than the plant part. And even though the leaders of the CCRC were plant people initially, Al Darvill, Pete Abersheim, they had the foresight to see that they needed to grow into the biomedical realm. And so they brought in people like Mike Tiamire, myself, then brought in people like Rich Steed and Lian Chun Wang and Ryan Weiss. And, you know, we recruited Bob Halterwanger. We recruited Jerry Art, you know, and Kelly Moorman and Mike Pierce were already here.

12:26And really kind of built up the biomedical part of the CCRC. So that, right, we kind of became the big dogs in terms of funding for a long time. But then things shifted again, right, because the biofuels, right, and remediation and using plants. And so there's been an expansion there. So now they're just two big, giant groups working together. I think, you know, for two people leading the CCRC that were plant people to have the foresight to say, we need to move into the biomedical realm, even though that's way outside of our expertise.

12:56That was really brave of them. And they started off with a two-grade hire, starting with Kelly Moorman and Mike Pierce. And they were just able to build on that. You know, I think it's a world-class organization now, right, that's extremely well-funded. You know, we've got great chemists like Hurt Jan Boone's unbelievable service facilities ran by Paris to Azadi that are cutting-edge technology. You know, companies and labs from all over the world come to the CCRC to learn how to do glycobiology or send their samples here. That's 100% due to Paris to Azadi being here.

13:27And then we've brought in people that aren't as glyco-focused but are method-focused like NMR, right, like Art Edison. Of course, we have technology people like Rob Woods on computing and Ron Orlando. And leadership's now changed, right? And it's actually led by more of an animal glycobiologist now, right, Mike Tiemeyer. And he's taken us in new and exciting directions, hopefully, and really trying to augment off the fact that the Center for Molecular Medicine is right next to the CCRC now, which is mainly focused on lots of stem cell differentiation, the use of stem cell technology.

14:01But there's so many places for the glycobiologist and the stem cell biologist to work together that he's really building, I think, building those relationships. And I think just like Pete and Al are able to see the future, I think Mike's probably going to be able to see the future, too, right, pretty well. And it's taking the Center in really exciting directions. It's exciting to see what we've done in the last 20. It's going to be really exciting to see what we do in the next 20.

Future of Glycobiology

14:26So far, we've talked about Dr. Wells' research, both in the past and currently. But what about the future? What's next for him and for glycobiology? Well, Dr. Wells has no shortage of big ideas. He sees glycobiology as the future of better medicine, cleaner energy, and eco-friendly materials. We're going to have better therapeutics, better diagnostics. You know, it won't surprise me if the plant biology people have fixed some of the recalcitrance issues and can really think about biofuels as a way forward to get away from fossil fuels.

15:00Also, biomaterials, I think, is an area that's really underappreciated. I mean, I think when everybody thinks fuel, you know, like fossil fuel, they think about gasoline. Everything that's made of plastic, right, which is everything in our life, right, is most of that's coming from fossil fuel, a lot of that plastic. And so being able to replace that with biomaterials that are, you know, A, we'll replace it, and B, that we can degrade when we're done with it, right, and it just doesn't end up in a landfill somewhere. So we're just trying to get away from this microplastic problem we're going to have, the one that we have right now, and it's going to get worse.

15:32I think there's going to be a lot of exciting things. We're getting so much better at big data. AI is going to change the way we do things. The data sets we're looking at a lot of times are just so complicated that the human eye can't see it all at one time. And that's something that AI can see pattern, you know, can see really, really complex patterns. I think that's going to really help us in terms of coming up with better diagnostics, better therapeutics, more personalized medicine. I think glycobiology is going to play a major role in that, obviously. Obviously, that's a biased opinion, but yeah, I think it's highly unlikely that we don't play a major role in that.

16:07That last point about AI is so relevant right now. I'm excited to see how it can further glycobiology specifically. Especially because glycobiology is so detailed with layers of sugars on proteins. AI might help us unlock a lot of hidden information. And it's amazing how Dr. Wells isn't just thinking about the future in terms of science, but also the next generation of scientists. So mentoring and just helping the next generation has always been really important to me.

16:38I was the graduate coordinator for biochemistry department here for 10 years. And then after that, I was the director of integrated life science, which is kind of the large umbrella program that all life science graduate students come in. I ran that for five years. And I've had 18 people in my lab get their PhDs in my lab. I've got eight graduate students in my lab right now. I always have undergrads in my lab, right? And I've had undergrads that have, right, we've had two win the Goldwater. We've had people graduate with their medical degrees from Hopkins and Stanford and University of Florida and, you know, all over the place.

17:14And, you know, just training the next generation. Actually, having young people in the lab helps keep me young. The thing is, sometimes as you get older, you have so much dogma that you've learned that young people will do experiments that I would never do. Because I'd be like, oh, that's not going to work. And they don't know that it shouldn't work, right? But then every once in a while it works, right? And it challenges the dogma. And so I think a lot of great ideas can come out of young people. That part where he said young people don't know what should or shouldn't work, so they just try everything. I love that.

17:46Same. It's such a great reminder that science needs fresh perspectives. For the young listeners who are interested in or just starting research, a mistake could very well be a scientific breakthrough. You never know. He's really made mentorship a priority. His lab has trained so many students who've gone on to do incredible things. Carolyn Bertozzi said it a lot better than I ever could, who won the Nobel Prize a couple years ago. Our job as scientists is not to try to be famous, not get rich.

18:16It's to train the next generation and make new discoveries. And all of that's going to outlive us. That's how, as a scientist, you make yourself immortal, right? Is by passing on the knowledge to the next generation. So I've gotten a lot of pleasure out of doing that. I like working with young people. They have ideas and thoughts that aren't sometimes burdened by knowledge. Not because they're not smart, just because they just haven't been exposed to it yet. And so they can come up with some really clever ways of thinking about stuff, right?

18:49It helps keep our ideas fresh, right? In the lab, which is important. Scientific immortality is such a powerful way to think about teaching and research. I know, right? The people that have helped me in my science and personal journey have changed my life. I am so sure Dr. Wells has had the same exact impact on so many people. So true. And it's not just about mentoring within the lab. He's also thinking about the bigger picture. Like with the massive NSF GREAT grant his team received. $18 million over six years.

19:22Most recently, we just got a grant that I'm PIA from the National Science Foundation. What are called biofoundries that they just got established. And so UGA, our UGA grant is for $18 million over six years. It's called bioF GREAT. And GREAT stands for glycoscience research education and training. And so the idea is that, like we said at the very beginning of this talk, a lot of people understand proteins. They understand nucleic acids, but they don't understand carbohydrates very well. And so we're going to be working with high school teachers to kind of inform them.

19:54We're going to be developing undergraduate material, graduate material. But we're also going to be developing research tools to make it easier to study in the lab. So the whole idea is that glycobiology as a field is undertaught in the classroom and understudied in the research laboratory. And so we're going to try to bridge that problem and see if we can provide tools to help it be taught more effectively and more broadly and for making it easier to study at the bench for labs that aren't, you know, glycophate-focused labs.

20:25It's kind of wild how undertaught glycobiology is, considering how much of our biology it affects. Exactly. I love how he's pushing this knowledge both inside and outside of the lab. I would have loved to learn about this in high school. Me too. No one should have to wait until a PhD to learn about sugars doing all of this cool stuff. And if you're someone who is just starting your science journey, I am sure Dr. Wells has some pretty solid advice. I've talked about a couple different things. One is you should do things you love doing.

20:57If you're doing something repetitively, right, whether that's graduate school or working in a job, right, you know, if you realize you're waking up every day not wanting to go to that job, you're doing the wrong job. Now, sometimes you don't have a choice in life, right? Sometimes you're not fortunate enough, but usually in graduate school, you're fortunate, right? I tell people if they're not happy in the lab they're in, there's one of two possibilities. A, they're in the wrong lab, right? They chose the wrong mentor. Or B, they're not supposed to be in a lab and they should go do something else with their life and be productive and happy. I find that people who are enthusiastic and love what they do have a tendency to be really

21:31good at it, right? I don't know many people that are really good at things they dislike doing, right? And so, you know, the other thing I always tell grad students when I was director is, right, look around the room. Everybody's smart, right? Everybody's smart. And so, are you enthusiastic? Are you doing what you want to do? And are you willing to put in the effort to get it done? You know, unfortunately, there's only so many hours in the day and graduate school takes a lot of those, right? And being a scientist, you know, I kind of wake up thinking about science and I kind

22:01of go to bed thinking about science in the back of my head. You know, Thanksgiving dinner, I'm like, well, you know, something pops in my head, right? And that's not to say I don't have a social life and that, you know, there's not a work-life balance, but you find that things that you're really passionate about and you love, you kind of think about all the time, right? What I wish for people is they find, whether that's being a scientist or being something else, is they find a job that's as rewarding to them as my job is to me. That idea of waking up every day excited to go to work, I hope we can all find that in

22:46our future careers, whatever we do. Passion really does make the difference. Yes. Sometimes people feel stuck in a role they have because they've already started down the path. Dr. Wells makes it clear that if you don't love what you're doing, it's okay to pivot. Definitely. Dr. Wells shows us that you can go above and beyond in any field you do. Science is just as much about people as it is about discovery. And with leaders like him in the field, the future of glycobiology is looking pretty bright.

23:18Leader, if you will. Thank you for listening to Let's Talk Chemistry, a podcast by Chemtalk. We hope you enjoyed it. For more information on today's episode and countless chemistry resources, please visit our website at www.chemistrytalk.org.