"Shape up Those Proteins--The Good, The Bad and the Ugly Amyloids"--Dr. Ann McDermott, Columbia University

Proteins are the building blocks of life. Our bodies make about 25-thousand of them.  Dr Ann McDermott, a biophysicist from Columbia University, studies the shapes of perteins as they clump into structures called amyloids.  Sometimes these amyloids stick to one another, forming amyloid plaques that can lead to diseases like Alzheimer's.  But Dr. McDermott and her colleagues are also looking at good amyloids that could lead science to develop new treatments for disease. She spoke at one of the "Town Talks" presented by Telluride Science. Veteran broadcast journalists George Lewis and Judy Muller moderated.

Transcript

Science Straight Up

Season 6, Episode 9

“Shape up Those Proteins—The Good, The Bad and The Ugly Amyloids”

Dr. Ann McDermott, Columbia University

Moderators: George Lewis and Judy Muller

(THEME MUSIC)

GEORGE: From Telluride Science, welcome to Science Straight Up.

JUDY: And on this episode…

ANN: (9:16) Shape is the language of biology. It dictates a function.

GEORGE: Time to shape up our proteins. our bodies are made out of them.  Ann McDermott, a biophysicist from Columbia University, studies the shapes of proteins as they clump into structures called amyloids. In her research she looks at the good…

(clip—“The Good, the Bad, and the Ugly” trailer)

GEORGE: While Dr. McDermott and her colleagues do differentiate between good and bad amyloids, they don’t hold beauty contests to figure out which are the pretty ones and the ugly ones. 

(crowd noise)

JUDY: Dr. McDermott was one of the scientists participating in a series of workshops put on by Telluride Science.  Here, scientists from all around the world gather to exchange ideas. 

MARK KOZAK: My name is Mark Kozak and I’m the CEO and Executive Director of Telluride Science and thank you for coming to tonight’s talk.

JUDY: And they also share those ideas with the community in what are called “Town Talks.” 

GEORGE: Judy and I are honored to moderate those sessions.

JUDY: We are so pleased to be introducing Anne McDermott to the town talks audience. You know, with so many problems on our minds these days, the last thing we need to worry about is our proteins. (laughter) Fortunately, Dr McDermott is doing that for us.

GEORGE: Most of us know that proteins are the building blocks of life, and some of us even know that the shape of those proteins is related to their function. In her lab at Columbia University, Dr McDermott and her team are focused on clumps of proteins known as amyloids.

JUDY:  And many folks I know are familiar with the fact that some amyloids are linked to diseases like ALS, Parkinson's and Alzheimer's and more. But our speaker is optimistic. The more she learns about amyloids and their shape shifting ways, the more promise she sees that this research can lead to designing tomorrow's medicines and even finding an upside to the shape shifting clumps.

GEORGE: Dr McDermott is a professor of biological chemistry at Columbia where she leads the McDermott lab. Please welcome her to the Telluride town talks. 

(applause)

ANN: Thank you. Thank you. Thank you. Thank you. Thank you.  Just as there's probably no way to have professional music without music enthusiasts. One of the things that the new federal administration has reminded me of, is that there's also the same statement equally valid with respect to science, our way of exploring how the world works, curiosity driven, basic research doesn't have to exist and won't exist if there isn't enthusiasm. And enthusiasts, it amazes me that you have this series, this town culture, this support. You keep it going, your podcast. I don't know anywhere else operating like this. I'm also specifically grateful to Telluride science organization Mark, Cindy, is that back there? Yeah, you're hiding the founders, Stephen Barry and Peter Solomon, the board, the supporters, y'all have found a way to bring together scientists for high quality conversations that would not otherwise take place and that enable great leaps forward.

But I have sometimes wondered if we're somehow a plague on the town. I got one version of an answer to that. The other day in your terrific, terrific bakery, a young man was helping me figure out how to get my coffee, and I was joking about being oxygen deprived, and he was figuring out, you know, my stuff. For me, one thing led to another conversationally, and I just asked him directly, how much of an annoyance are the scientists when they come into town? And he said, Oh, no, you guys are no problem. It's nothing like the festivals. First of all, the scientists, they don't know what's going on. They're clueless. Secondly, they have very low expectations, and they're just not that many of them. (laughter) Anyway, that's a thank you. 

You said you said it so well. Proteins the building blocks of life, yeah, it's the stuff in supplements for gym bros and specific amino acids, but they are also the molecules that are responsible for almost every process of life. You make about 25,000 of them, and for every cause, every cellular and biological need your body makes a bespoke protein, one for digesting the fats in your food, one for carrying the oxygen from your lungs to your muscles, etc. Proteins are long, slender molecules as born like spaghetti, but to carry out their function, the protein does not remain a long spaghetti noodle. Rather, it folds up to a unique and compact form. The shape is the most determinative feature of the protein. Shape is the language of biology. It dictates a function.

JUDY: And when those proteins clump into amyloids, watch out, because they can do things like causing plaque buildups in the brain, leading to Alzheimer’s Disease. Amyloids were in the news recently when the Food and Drug Administration approved a new blood test for the early detection of Alzheimer’s.

GEORGE:  Frank Mc George, M.D. covers medicine for WDIV in Detroit.

DR FRANK MC GEORGE: Amyloid plaques in the brain, they’re a hallmark sign of Alzheimer’s disease. Now, these plaques can be detected using a pet scan or a spinal tap but those are costly and carry other risks. But now, the FDA has approved the first blood test to diagnose Alzheimer’s Disease.

JUDY: That could lead to earlier detection of Alzheimer’s, a disease that affects almost 7 million Americans…a number that’s expected to grow as the population ages. Ann McDermott says when amyloid plaques appear, they’re caused by the way those proteins shape up.

ANN: Sometimes, after adopting a specific, beautiful shape, a protein can essentially change its mind and shift out to another shape, another shape that is elongated and therefore sticky, and it sticks to another copy of the same protein. And then another and another, and finally, thousands of them, in a very orderly fashion, make a big plaque.

GEORGE: And it isn’t just Alzheimer’s. Amyloids can bring other diseases, including contagious ones.

ANN: Pathology is what taught us that we have amyloids, a disease that is based just on the shape of a protein, that that's a disease. This is a very weird basis for the very weird Mad Cow Disease, Kuru and many other diseases that are contagious without the presence of a normal vector, without a bacteria, without a virus, without even any DNA. Such a problem can occur for many, many different proteins collecting in many bodily organs, typically outside of the cell. In many diseases. Neurodegenerative diseases come to mind, Alzheimer's, Parkinson's, ALS diabetes in the pancreas, or cardiac amyloidosis, heart failure based on an amyloid molecule thickening and stiffening.

JUDY: In the contagious diseases, the amyloid proteins can form seed like structures that pass from one host to another.

ANN: And if a seed like that somehow gets transferred from my fluids to your fluids, I can transfer to you this contagious disease of clumped proteins. My proteins could teach your proteins a bad trick, and then you may carry my disease. Disease contagious without any normal vector, without any bacteria, no virus, no DNA. Now, besides being called an amyloid on the basis of its shape, these are also referred to as prions.

GEORGE: Remember the outbreaks of Mad Cow disease that affected the United Kingdom in the 1980’s and ‘90’s?  That was caused by misfolded proteins..those prions that cattle picked up and transmitted to humans who ate their meat. The consequences… fatal.

ANN: And therefore the disease can be contagious and jump from cell to cell and from patient to patient. Stanley Prusiner won the Nobel co won the Nobel Prize in Physiology and Medicine back in 97 for this theory, of course, developed, like all breakthroughs by many meticulous contributions from many, many laboratories.

GEORGE: Now, what if science could come up with ways of designing good amyloids to fight off disease?  Ann McDermott says a lot of people are working on that. One possibility...utilizing killer proteins that would help the body’s immune response eliminate the bad amyloids.

ANN: There's a protein whose name is rip k1 and it sticks to another protein called rip k3 and rip is an acronym, and I was told not to use acronyms today, but this one is supposed to be funny, because it stands for rest in peace, and this is a cell death pathway, but also it stands for Receptor Interactive Kinase.  Projects in industry and academia seek to design drugs to stick to these rip proteins and thereby control the innate immune response, inflammation, autoimmune disease, cancer, all of which share some of these events.

JUDY: In developing those drugs, researchers are trying to find ways to keep viruses from fooling the immune response. The amyloids form spine-shaped structures, designed to fight disease. But sometimes, viruses will disable them.

ANN: The virus, the very guy you're trying to hide from, makes a protein that can join this spine, gumming it up, decorating it at the ends, stopping it from doing what it wants to do. The complex of the viral protein together with our rip k3 effectively says to the cell, we're good. No, we don't need the immune system. We're just a little virus factory here. No need to send in anybody, cat and mouse, or rather, virus and man and point for the virus, which has already found a way around our immune system. 

So I'd like to end where I started, with gratitude for your participation and eager to hear what your questions are.

GEORGE: Judy and I kicked off the questioning.

JUDY: I was thinking back to…we speak to the scientists before this evening by zoom, and we try to get an idea of things to ask and what you're talking about. And when you talked to us earlier, you talked about the scientists, I think you said, have known for more than 100 years that clumps of proteins, amyloids, cause diseases. Is that correct?

ANN: Yeah, so although we didn't know what they were, they Yeah, the word amyloid refers to the fact that they thought maybe even they would be carbohydrates, but yeah, they knew they were in there, and they knew they were disease related. 

JUDY: Yeah. Okay, so now you're saying that you're studying ways that these amyloids, these clumps of molecules, can actually be forces for good. And I'm wondering if that is a fairly new, revolutionary, controversial concept is, how new is that?

ANN: I would say there was a higher burden of proof than some other discoveries when that came out. I mean, it was surprising people, people were fighting that and for these examples from the human biology same I think we're still greeted with appropriate skepticism. There are other examples that have been proposed, including a protein we studied with Eric Kandel, who's known for his work on the difference between long-term and short-term memory. Has a Nobel Prize for that work, and, he thought about the possibility that what cements something into being a long-term memory is that a key protein becomes an amyloid. Now those amyloids are right at the doorstep of your your brain, and the place where amyloids cause the most trouble, that's a weird idea, and so they should be greeted with serious skepticism. And I think there's still a little debate that goes on around that one. Yeah.

GEORGE: In doing my homework for this evening, I saw that your studies involve a special technique called NMR, nuclear magnetic resonance is this related to MRIs magnetic resonance imaging that many of us have had to undergo?

ANN: Can we show George some love for asking about NMR? Yeah. Yes, yes. (big applause) 

GEORGE: Do we have the NMR lobby? Here?

ANN: We have the NMR A team here in the house? Yes.

JUDY: While an MRI looks at parts of the human body, NMR looks at molecular structures in chemistry and biochemistry. The principles are similar, using heavy-duty magnets to study tissues or tiny molecules. It gives scientists a way to look at proteins within cells and figure out what shapes those proteins are taking.

GEORGE: Are you guys busy creating databases of these different shapes, so that they can be automatically recognized by computers?

ANN: And you can play with those shapes. That database is maintained at Rutgers right now and other mirror sites in the world. And you can go and have a field day just looking at what they look like. And they're nicely rendered. And you'll see that some of them, if you read the fine print, were done by NMR and the majority were done by X ray crystallography or another newcomer called cryo em, and that's how you could have AI tools to predict the next protein is because it stands on the shoulders of the people who who did the structures. 

JUDY: So have you ever been surprised, kind of Eureka, by anything that you didn't expect to see using NMR? Have you been a bit in awe of that?

ANN: Oh, I think we all have like, yeah.I think a lot of us fell in love with NMR because it turns out to be something that really illustrates that quantum mechanics is right. It's not just a story. So, we love it for that reason. But when you start to apply it for proteins, the thing it does for you that the other methods don't Is it really shows you what's moving and what isn't. And sometimes you don't see that coming, right? You're all ready for a still life, but it gives you a hint of what a movie would look like. And so the moving parts of our protein, we get pretty excited about that. Yeah.

JUDY: Okay, so we talked about ALS. We've talked about the diseases that amyloids can cause and Alzheimer's. is there any advance work in seeing how that can be disrupted and any kind of solutions for those diseases? 

ANN: Yeah, yeah. So there are a number of therapies that are like early on, and I do think that if you follow that story closely, you could feel a little bit like Charlie Brown and the football. They've been promising things, but a lot of the therapies are based on small molecules. But what's maybe more exciting right now are the so-called biologics. So when I say a small molecule, I mean something that a synthetic chemist could cook up in a flask and it might have, oh, 100 atoms, okay, maybe only 50. But a biologic means an antibody that is prepared preparative scale and and administered as a as a drug. And those can be so, so specific, you know, that could distinguish the amyloid form versus the soluble, normally folded form. Those are showing a lot of promise as therapeutics. In some cases, you see something where it would halt the progression further, but it doesn't necessarily. We're hoping for the home run of gradually cleaning up all such plaques. And so this is a story to keep watching.

GEORGE: We've been reading stories about how the Trump administration has gone to war against universities. Columbia is one of them. Has that affected your work?

ANN: Oh, of course, yeah, yeah. And there were different stages. And there was not knowing what's coming next, and living with that and preparing for everything, and a lot of loss of sleep and and I worry my. About how it's been affecting the younger people, the talent that we have in our labs, and what do they want to do next? That's, that's my biggest worry. That's where I lose my most sleep. 

JUDY: Are there jobs waiting for them, though?

ANN: Academic jobs? We're still hiring who wants to come work at Columbia? (laughter) Yeah, no, there will be. There will be, I don't, I don't think we've seen the end of this story. We don't know what's coming next, and they're rolling through university after university, taking ransom money and trying to scare us. But I don't think this country wants to give up its crown jewel of higher education that easily. I don't think that's what we want.

JUDY: Well, we’d like to open it up to the audience for questions. There’s one right here.

MAN IN AUDIENCE: Amyloid plaques from amyloid proteins…is there an uncontrolled growth mechanism at play, which is similar to those that would give rise to cancer? And if so, are there treatments available that could be used for amyloid plaque prevention that are currently being developed for treatment of cancers?

ANN: There is cross talk in the systems that are involved with cancer and those from the immune system, and  a lot of cross talk between different systems. So you could, you could see some of this touchdown on cancer. 

GEORGE: There’s a teenager named Gabe who’s been coming to these science talks since he was a little boy. Ann McDermott was rather impressed by his question.

GABE: I was curious when you were talking about the innate immune response, amyloid you were just or were researching that functioned as the cell killer, when you mentioned the virus or bacteria, the bad response that could block that cell killer formation from occurring. Did that like, does that have a potential for, like, copying that design in viruses and applying that to the bad amyloids that happen in the brain, and like using that to stop the formation of amyloids, we don't want?

ANN:  Come join the lab. That's a cool question. That's a very cool question. That kind of area we need, we need more work, right along those lines, yes, please. 

JUDY: I was just gonna say you're back. Have you graduated from college?

GABE: High School

 JUDY: High school. He's been coming since he was like little and so exciting to see you growing your questions. That's a cool question.

MARK KOZAK: Gabe Walther everyone.

GEORGE:  Let's hear it for Gabe. (applause) 

JUDY: anybody else?

GEORGE: I-I want to ask you, at what age did you first become attracted to science, and how did that all come about?

ANN: Oh, wow. Okay, I think for a little while I assumed I would study and pursue music, probably because that's one of the few things we were told not to do by our parents. And by then, my dad brought me into his work. He was a person with no education, and I mean not even grade school. And he was one of the chief engineers on the subway system, and in Washington, DC, the metro system, and he was doing some pretty cool things at the time, and he invited me in to his office, and I learned a lot about him. And then he told me to file, and I wasn't any good at that. And then he told me that I could do something a little bit technical and do take off work from blueprints and estimate how much they needed to order of something. And then at the end of this week, he said to me, you know, I think you should go to science school. And I said, what. I said, What? And then I decided, for once to follow some advice. And when I got to college, which at that time was Harvey Mudd College, which at that time had no girls, it was very small and but they gave me, they gave me a scholarship, and I met a lot of really cool people there. And gradually I fell in love with biophysics and especially the idea of non-invasive ways to find out what was going on inside the body. So many points I thought about going back off that track. But then some puzzle or some beautiful phenomenon would hook me right back on.

JUDY: Were you, were you one of the first women at Harvey Mudd, then?

ANN: Not one of the first but let's say many classrooms, I would sit down and I would look around and I wouldn't see another one. Or yeah,

JUDY: How do you see that changing in your own classrooms?

ANN: Oh, it has changed. The faculty are still not representative, but our students are close to. At Harvey Mudd, it didn't change by drift or automatically. There was a wonderful president, Maria Klawe, who walked into that place and said, This doesn't make sense, and let's stop let's stop this. So sometimes it's just to creep in, because the world has changed, and sometimes it takes a real leader. But yeah.

JUDY: Do you have a question?

WOMAN IN AUDIENCE: Yes.

JUDY: She does.I knew it!

WOMAN: Does your research help with having any hope, for instance, with the most pervasive disease, Parkinson's disease, we live in a continuing care retirement community in Virginia, and the amount of people that have been diagnosed with this disease, and it's different in every person is just mind boggling. Does your research have any hope with helping figure this whole disease out?

ANN: Thank you. I mean, I don't think there's a person who hasn't been affected by that right one of our loved ones, or it's hard, it's hard to think about and to experience and observe. I think that the field, in aggregate, will, that you accuse me of being an optimist, and that's not wrong. But look, I think, and when you think about basic research, maybe 1% would be a high number for how many of our projects will ever become translational okay? And I, I'm not a person who's ever pushed that within myself, it may happen. I It's not my dream. But on the other hand, if you say, how many cool new high-tech companies would happen without the basic research, if you flip the question around the other way, I would say, not that much. Not that much, right? So even though maybe only 1% of our projects lead that way. I think that's that is the path.

JUDY: There’s one right here.

WOMAN IN AUDIENCE:  I didn't hear much about causation. So I'm wondering, what if you're working at all on, what makes a bad protein turn into a good protein turn into a bad protein. I mean, was it abused by its mother? (laughter) Did it lose its grant?  Did it get jealous of something? What causes it?

ANN: So high concentration, not staying folded very well, the stress on the cell, the cell being too acidic. It might be that there was a mutation. Okay, so, so if that sounds like a vague laundry list, it is because we don't know as much about this as we want to.

GEORGE: If you can, if you can figure out what's going on at the protein level, will this lead to new diagnostic techniques to catching diseases at an earlier stage than medical science can now do? 

ANN: I think that's equally important as a new therapeutic. equally important because many of the existing and early-stage medications, they just stall the progression of the amyloid. They don't. Uh, roll back and remove. Okay, so early diagnosis is super, super important, and I think it will only become more important over time. And so it's complicated, like researchers have shown that there isn't just one kind of protein making a plaque in Alzheimer's. Okay, yeah, yeah. They're different strains. Okay, so knowing what you're dealing with, this is kind of like the buzz word personalized medicine, you know w, knowing the very specific strain you're dealing with, and all that, I think, will be very, very important. And so how do you get those diagnostics? A lot of times it's, it's very good to be able to create that object in the laboratory, on the bench outside of a cell, and to characterize it carefully. And so that kind of that kind of work, including getting the shape right, including, as we say, determining the protein structure. That kind of work will be a big assist, I think.

JUDY: Fascinating.  Well, that’s all the time we have. Please give a big hand to Ann McDermott.

(applause)

(fade in theme music)

(GEORGE) A big thank you to Telluride Science for making Dr. Ann McDermott’s presentation possible and to our sponsors, Alpine Bank and the Telluride Mountain Village Owners’ Association. 

JUDY: Dr. McDermott appeared before a live audience at the Telluride Conference Center in Mountain Village, Colorado and Colin Casanova was our audio engineer.

GEORGE: Mark Kozak is Executive Director and CEO of Telluride Science and Cindy Fusting is Managing Director and CFO. Sara Friedberg is Lodging and Operations Manager and Annie Carlson is Director of Donor Relations.

JUDY: If you want to donate to the cause, go to telluride science dot O.R.G. That’s also where you can find our podcasts or… look for “Science Straight Up” on your favorite podcast apps. I’m Judy Muller…

GEORGE: And I’m George Lewis, inviting you to join us next time on “Science Straight Up.”

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