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Intro/Outro (00:01):
Welcome to Cryo-Talk a Bitesize Bio Podcast sponsored by Thermo Fisher Scientific featuring conversations between your host, Eva Amsen and experts in the field of Cryo Electron Microscopy.

Eva Amsen (00:14):
Today on Cryo-Talk, we're joined by Joachim Frank Professor of Biochemistry and Molecular Bio Physics and of Biological Sciences at Columbia University. As we discuss his Nobel Prize winning discoveries.

Joachim Frank (00:28):
It was a very, uh, instant glimpse that this could be used in, in image processing.

Eva Amsen (00:36):
His second career as a fiction writer.

Joachim Frank (00:38):
Oh, it's a novel about a, a scientist of course.

Eva Amsen (00:42):
Why he loves living in the Berkshires.

Joachim Frank (00:45):
So they're very interesting people from all fields of, of, of science and arts.

Eva Amsen (00:50):
And the importance of always using your peripheral vision.

Joachim Frank (00:54):
You, you just don't know what opportunity has come along.

Eva Amsen (00:59):
All in this episode of Cryo-Talk.

(01:06):
Hello, I'm Eva Amsen, and I'm here today with Biophysicist Joachim Frank Professor at Columbia University and recipient of the 2017 Nobel Prize in chemistry for his work on the early development of Cryo EM. We are going to talk a bit more about that later, um, but first Dr. Frank, how are you today?

Joachim Frank (01:26):
Fine. Fine. Thanks. Thanks very much for having me.

Eva Amsen (01:29):
We're glad to have you on the podcast. Um, can you tell us a bit about what, um, you're currently working on or what your group is currently working on?

Joachim Frank (01:38):
Um, well, uh, there are, um, a number of time resolved Cryo EM Projects, um, and, uh, this time we are working on, uh, eukaryotic translation, uh, different steps and eukaryotic translation, uh, previously we worked on, uh, E-coli, uh, translation. And, uh, so this is a major switch.

Eva Amsen (02:08):
Yeah. Sounds uh, really interesting to really figure out all the, the mechanisms behind it. And, um, as I mentioned, you, you got a Nobel Prize a few years ago for work that you did many years ago in the, um, early development of Cryo EM and, and that work was in the, the pre-Cryo EM day. So can you tell us a little bit about how that connects to, um, what, what now people know as Cryo EM?

Joachim Frank (02:37):
Well, um, this was, uh, this was very interesting and exciting, um, uh, pioneering time when, uh, we had to make do, uh, without, um, a, a very, very good, um, means of supporting, uh, molecules. So we used a negative stain and negative staining is, is really not, not a very good method to preserve 3a structure. And so, um, it, it, it was a great challenge from, from that point of view. Um, and, uh, so, uh, nevertheless, we, uh, essentially we, we got it done. Um, the trick is I think, uh, with negative stain that you, uh, you choose sections where you get, uh, a full coverage with a stain, so that you can get at least preservation of, uh, of the entire structure, even though it's distorted, it is always distorted, it's always collapsed in the, in the D direction.

Eva Amsen (03:48):
So it's a, it's, it's a lot easier now to image than it was for you back in the days.

Joachim Frank (03:53):
Yeah, absolutely. And, uh, so this, this, this is actually, it's a major challenge in, in with a whole idea of single particles because, um, since they're not, the molecules are not sitting sitting together or they cannot, um, they, they're not sort of fully stained normally. So each molecule is individually stained and, and each, uh, has its own way of getting stained, you know, so, so there's a lot of variability and that, that actually was interesting because that variability, um, uh, was, uh, was interesting from the point of view of, of, of looking at, at the multivariate statistical, uh, aspect of it. So it it's possible, uh, you know, at the time when we developed multivariate statistical analysis, which, which was 1980, 1981, um, it, the, the first, the first really very dominant thing that kind came out when we looked at, um, molecules in stain is, is a very big variability in stain distribution at the periphery. So, so you get, you get some, um, uh, you get molecules on one side that, that are, uh, that are only, um, you know, halfway, uh, in the, in the puddle and the other ones are, are completely immersed. It's a very, that's a very interesting aspect of, of, uh, heterogeneity.

Eva Amsen (05:48):
Yeah. Yeah. So, and, and, and your, your work from around that time was very much about like being able, I guess, to average the image and, and get a sharper picture. Am I summarizing that in a way that makes sense?

Joachim Frank (06:01):
Well, the, the, the two dimensional, uh, proof of, of, of getting, getting much enhanced, uh, two dimensional information was, was the first proof of concept. Uh, I mean, so the, uh, the proof was, uh, to get, uh, successful alignment of, of, of images. And then, um, uh, yeah, that was essentially a first thing. Uh, we could get sharper information out, but then the next step was, which was really a real milestone is to, uh, be able to differentiate between molecules that have different appearance. And then, so, so then you get, you get really very sharp images of subsets and that, that was a big breakthrough. And I think, you know, in terms of, of, um, credibility of the entire method that, that really made, made a very big difference. Yeah. So that happened in 1981.

Eva Amsen (07:08):
Yeah. And I mean, it's, if you think about what people are, are looking at right now, it's so often really is about distinguishing the, the tiniest little differences and, so there's a lot of information in that. Um, so over the course of your career, you've worked in, uh, in Germany and the US. Um, can you take us very quickly through that journey?

Joachim Frank (07:30):
Uh, well, it was a very big, uh, very long journey. Uh, I was, uh, I was first in, uh, at the University of Freiburg, uh, and got my, uh, Fordiplom. Uh, so they, the Bachelor and, and I majored in Physics. Uh, and then I went to Munich and did a Masters, um, a at a place, uh, a at the [inaudible] Institute, um, where, uh, I worked on, uh, a project of, um, um, looking at the back scattering of electrons on liquid gold. Um, so, uh, that was a very big experimental challenge because you had, if you can think of it, you have to keep gold, uh, at a, at a melting temperature, uh, in a vacuum where you also do measurements of, of, uh, uh, back scattering of electrons. So this, uh, was an incredible experimental challenge. And then, but that introduced me to electrons and, um, and electron, um, you know, I had to, to build a little electron gun in the process, so that sort of steered me in that direction, but also the, uh, the mentor that I had, uh, Dr. Kinder, um, uh, was one of the pioneers in, in biological, uh, related electromicroscopy, he, he discovered the, um, the patterns of, of, but of scales on butterfly wings in 1943. Um, so which, which produce color by interference, uh, effects, uh, and, and so, so he had an, he had an instrument, uh, an, an old electron microscope in his office, uh, that looked like, uh, the canon of Peter's, uh, Peter's, moon, uh, shot, you know, the children's book. Um, it was, it was mounted, uh, it was mounted, uh, horizontally, uh, slightly coming up to you to the observer. So the, the screen, the screen was in front of you and the, and the, and the cathod was, was at, at the very far end.

Eva Amsen (10:12):
And how, how big was it?

Joachim Frank (10:15):
Well, it was, it wasn't, you know, normal column size, but, but it was, it was, uh, mounted, uh, you know, slightly upward horizontally, uh, facing, facing you. Um, so, so then, uh, since I wanted to stay in Munich, um, I, I, I had to, I had to find a place where I can, could do electron microscopy, um, and, uh, so, so that's how I, I wound up with, uh, Hopper, well, The Hopper. Um, so while The Hopper, uh, had an Institute, uh, for, uh, structural research, but, but he was an x-ray crystallographer who, who, uh, uh, discovered an interest in electromicroscopy. So he, he applied all the different concepts of x-ray crystalography in, in, in electron microscopy. So, so there's a lot of work that I, a lot of theoretical work that, that he did at the time. It's very, it looks very esoteric if you, if you take a look at it's very, very esoteric. He had, he had incredibly high flying ideas, but, but, uh, they could not be realized at the time. Many of them could not be realized at the time. So that's how I spent, uh, time and, and I, that's where I got into image processing. Um, I, I, uh, did the first image processing with micrographs and, um, got, um, you know, uh, discovered that one could use correlation functions in order to get, um, alignment of, of images and, uh, uh, found out all, all kinds of, all kinds of theorems, uh, I, I studied, uh, statistical optics, um, and applied some of the, theorems in image processing. And so that was really the beginning. And then 1970, I, I got the, I got a PhD and in the process, um, I, I got a nomination for a Harkness fellowship, uh, that brought me to the United States for two years, and I could select any labs that I wanted, uh, to go to. And so I wound up at the Jet Propulsion Laboratory first, and then I went to lab Bob Glass's at Berkeley and then at, uh, Cornell University. Um, and a very interesting time was at the JPL, uh, Jet Propulsion Laboratory, because at the time they had the most advanced image processing equipment in the world. Uh, so, um, you know, I, I could do scanning and, and also, uh, making images again from the computer, you know, which nobody could do anyway, you know, we, we, we, we did over printing over printing of characters, uh, before, before that.

Eva Amsen (13:42):
Wow. Yes. That must, that must have been so interesting to, to be at a place that was really at the, at the forefront of technology.

Joachim Frank (13:50):
Yeah. Yes. And, and I, I, uh, I used, I used the image processing system VIKOR, uh, not, I, I didn't, it didn't just, it didn't use it, but, but rather I use it as an infrastructure to, to port my, my programs in. And so, so I had an entire infrastructure, which, you know, did, uh, suit or do loops and, and things like this. So I hooked my programs up and it was very, uh, very, um, very advanced kind of way of, of, of using software. And then later on, later on these ideas that I found in, in the software development, I applied in the development of SPIDER.

Eva Amsen (14:39):
Has there ever been a moment, um, at any point in your, your research or career where things took a surprising turn for you.

Joachim Frank (14:48):
Always, always, yeah. Yeah. I told you about how I, how I ran it to electrons and electron microscopy and, you know, and I, I went up with Hopper only because, because I wanted to stay in Munich because I thought it was an interesting, uh, place to be. And, uh, later, you know, the, uh, there's a story about the multivarious statistical analysis, um, that, um, it, it was, it was a sheer accident how, how, how we developed this. Um, and, you know, it was, uh, spurred by somebody working in a breath sample analysis. And because multivarious statistical analysis had been used for a very long time for, uh, for, for this kind of, uh, for, for, for specimens, medical specimens. And so, so they sort of, there was a very, uh, instant glimpse that this could be used in, in image processing. And so that was very exciting.

Eva Amsen (16:03):
Yes. It, it's funny how, how things end up, like you make a, you make a choice for one reason and it ends up, uh, completely definding the course of your career.

Joachim Frank (16:13):
Right. That's, that's why, you know, there there's a lot of, I, I get, get a lot of questions from, from students. Uh, you know, is there something special that, that you wanna convey to us? You know, what, how, how can one be successful? And, and then I, I, I say peripheral vision, you know, keep the peripheral vision open. Uh, don't just, just, uh, follow some one, one specific plan because you don't, you, you just don't know what opportunities come along and you, you just so have to keep an very open, open eye.

Eva Amsen (16:53):
Yeah, that's definitely true. Um, and if we go back to, um, Cryo-EM for a bit, um, is there anything that you're very excited about, um, where the field is going at the moment?

Joachim Frank (17:05):
Um, well, you know, the, the, uh, the fact that we are now, uh, coming, getting something, the two angstrom range, um, if, if we do things right, if the sample behaves right, uh, that that's very exciting because then really Cryo-EM, um, can contribute to drug development and so forth. It's really the, the, uh, uh, the right direction. And, and, um, I don't know what the purpose of going to one angstrom is. Uh, I mean, it, it becomes more, more esoteric. Um, and then, so, so lately I'm, I'm really very interested, interested in, in the Cryo, in the, in the time resolved, uh, technology I've contributed to it. And, and I think, uh, that it's, it's probably going to become mainstream, uh, when, when the, the kinds of instrumentation is, is generally available. And so I'm working myself on, on this, I'm working in collaboration with a, with a company to make that happen. And, you know, we're trying to get into an, we are trying to get into a price range where, you know, becomes competitive.

Eva Amsen (18:36):
Yeah, yeah, yeah. It's definitely exciting times also for, um, yeah, I guess people will be able to use it for so many more applications. Uh, yeah.

Joachim Frank (18:45):
But, and then the other, the other, um, developments that, that I've I've been involved in is, is the, uh, mapping the mapping of, uh, confirmational space and, uh, you know, state space and, uh, uh, to, um, to map the, uh, free energy landscape of a molecule. So that's, that's an, um, it's a very fascinating aspect of, of Cryo-EM because you, you get such large, uh, samples of, of molecules. You can get millions if you want to. Yeah. And, uh, then, uh, a deep data analysis and, uh, machine learning, uh, can, can give you, uh, a sense of the confirmation variability, and you can then analyze it to, uh, to get free energy landscape. And from there, you really, you can explore, um, the, uh, the functional movements of the, uh, of the molecule.

Eva Amsen (20:00):
Yeah. Wow. That's, that's, that sounds like something that's like, thinking back to my own days of studying chemistry and biochemistry, that just seemed completely impossible.

Joachim Frank (20:11):
Yeah, I have a, um, I mean, if, if you want, want me to just illustrate this with a few word words? Uh, my, my favorite example is, is if you, uh, I, I found a, I found an image, uh, was from somewhere in China. There were where, where 10,000, uh, horses, were galloping over, uh, you know, through a landscape. And of course, one, couldn't see the 10,000 in this picture, just this upset, but you could see them going into the horizon. And then just, just imagine you have somebody standing somewhere, a tourist, and it takes pictures. Um, and it takes, you know, a whole lot of pictures or you, in fact, you have many people standing there and they're all taking pictures from their direction. So then, and so then the challenge is, uh, you go home and now you, you try to sort these pictures and they're all galloping. So, so you could, you, you should be able to get, um, for each, for each horse picture that you have, there's always a before and then after one of, of any other horse. Okay. So you can order them in the sequence of Gallop. And then, so you can, you can actually extract from there an entire sequence, the, the entire, uh, work cycle of, of Gallop, uh, from, from all these horses. So that's, that's really what we can do. Um, if, if we have some, you know, confirmational movement of molecules, which are multidimensional, and then you can, you can order them, you can order them in, in the different dimensions and then, uh, can in the end get, get, uh, information about work cycles and so forth.

Eva Amsen (22:12):
Wow. That sounds amazing. Um, so we talked a bit about, um, what you see the, where you see the future of the field going, but, um, what about yourself? Do you have any plans for the next few years?

Joachim Frank (22:28):
Well, I'm, I, I was, um, very, um, lucky to get, uh, to get another big grant. And so I'm, I'm gonna, I'm gonna be able to, uh, realize a number of my dreams, uh, you know, in terms of time result, Cryo-EM and so forth for the next, um, the next four years. And that's pretty much my, sort of the milestone of, of retirement, probably.

Eva Amsen (23:02):
One big project before you retire, is that, and, um, I, I understand that you also a novelist, can you a bit about that?

Joachim Frank (23:13):
Well, I've been dabbling in, in, uh, fiction writing for a very long time. Um, I, I got very excited when, when I discovered that I can really write, write English, um, as a second language in a way that would be recognized. And, and, you know, I, I probably was able to publish short stories and so forth. And then, and then I have written a number of novels and, uh, one of them is, has been published, uh, in, in 2019. And, uh, so it's available now. It's, it's called Aan Zee but it, but it's really, um, uh, I, I wrote it a long time ago and, and had to rewrite it very often. Uh, it's, it's fun to read. I think it's an, uh, it's a novel about a, a scientist, of course, but, uh, it, uh, it doesn't have a lot of similarities with me, but, uh, but it benefits from, from the whole, uh, knowledge that I have about the, about how science, how, how, how the heads of sciences work and, uh, what, what makes them excited and so forth.

Eva Amsen (24:34):
Yeah. And, and is it, um, did you start writing as kind of a distraction from research, or do you see, um, writing fiction and thinking about science as somehow using the same creativity?

Joachim Frank (24:48):
Yeah, I think so. I think so. Uh, but at the same time, I, I, I would, I would be unable to confine my, my whole being to, uh, to, to science. That's impossible. Uh, I, I really need, need this as an I, I wouldn't call it distraction. It, it's rather a sort of a compliment of, of, of my whole, uh, existence.

Eva Amsen (25:18):
And, and can you tell us a little bit about the picture that's behind you at the moment that we can see?

Joachim Frank (25:23):
Oh, right. Um, well, this is, uh, um, this is a picture, um, it's a collage, uh, that's supposed to look like a butterfly and, uh, it was done by my, it was a present by my daughter, uh, when she was in high school, this one of project, she, she did really absolutely beautiful things. She, she, um, she started, she started drawing amazing things when she, when she was little, when she was maybe eight, ten years old and so on, beautiful, beautiful things. I, I have large collection of these. And then in high school it became much more, uh, elaborate. And then I, I, I always thought she, she would, she would somehow get into area of art, but, but she didn't, she got into linguistics. And, uh, and now she is in a Code, uh, in a, in a Code Academy. Um, so she is, uh, she is in a, at a place where she, um, uh, you know, develops curricula for code, uh, developing.

Eva Amsen (26:41):
Yeah. So you've always like encouraged, um, your children to be creative.

Joachim Frank (26:46):
Oh, yeah, yeah, yeah. That's really because for me, for me, this is really sort of the essence of, of, uh, my, uh, you know, day to day, uh, existence. I, I really, I enjoy looking at things. I enjoy taking pictures and bring them into contexts in different contexts. I enjoy the juxtaposition between images and texts. Uh, that's very, uh, you know, you, you, there are essentially three ways how you can explore this. Uh, one is, is that the, uh, the image is an illustration of the text. And the other one is that the text is a legend to the image. And the third one is, is that, you know, you take deliberately two completely unrelated image and text together, and then you, you, you find out that in the, in, in, in, in, in the, the person who, who looks at it, you immediately start getting a new gestalt from this. You, you, you they're immediately seen as in some way related, and that relationship is sort of created in your brain. And, and, and so this is, this, this kind of, this kind of exploration is very exciting to me.

Eva Amsen (28:23):
Yeah. And I guess, and people don't tend to think of science as being creative, but it is of course, very much related to images especially imaging work, so. Um, I've got a few short questions for you now it's, uh, quick-fire questions, but if you wanna take a bit longer about one of the answers you can, um, so first you you're at Columbia university, which of course is in the middle of New York City, but do you personally prefer the city or do you prefer the countryside?

Joachim Frank (28:55):
Um, uh, both. I, I prefer both and I, I'm in a very lucky situation that I'm right now I'm then the countryside, I'm at a house that we have in The Berkshires. Oh, nice. And, uh, so we have an apartment in New York city and, uh, we have this house here and of course we spent, we spent most of the time in the last two years here at the house for obvious reasons. And, um, and, uh, but, uh, but I mean, the rural environment is really, really fantastic, especially The Berkshires, uh, where you have a little of both, because you have a lot of retired people here who are, uh, you know, maybe 60% come come from New York city then. And so they wanna keep an, an intellectual, uh, environment going. So they're very interesting people from all fields of, of, of science and arts. And, uh, and in The Berkshires, they, you have Tanglewood and, and Jacob's Pillow and, and, and all this. So I, you know, I, I, I love to be here, but at the same time, the urban environment, uh, in New York City, this Cosmopolitan place is, is really wonderful. It's really wonderful for someone who comes from Europe. And it, it, it is really, uh, more European than Europe, uh, actually, because you have, you have this cross cultural interaction there.

Eva Amsen (30:43):
Yeah. Yeah. It's like its own little, little universe. Um, do you like cooking at all? Do you, do you prepare your own food at home?

Joachim Frank (30:54):
Oh, that's an interesting question. Cause I, I, I got, um, I mean, my, my wife is, is such a fabulous cook, uh, that I, I can't, you know.

Eva Amsen (31:04):
She won't let you?

Joachim Frank (31:06):
No, no, not that she won't let me, but, but I'm, I'm sort of, I, I, I can't keep up with any, any like this. Uh, so I used to just make myself spaghetti and so forth, but, but now, but now I just, um, my, my daughter, um, you know, just, just, uh, gave me very detailed instructions for a, for a certain dish. And, and, uh, and so I'm, I'm excited to really get into that. And then I watched, I, I, I forced to watch some of the British, uh, show, uh, and, uh.

Eva Amsen (31:48):
Bake Off? Great British Bake Off?

Joachim Frank (31:49):
The Great Bake Off. So both, my, my wife and my daughter watched it, watched every single bit of it. And, and sometimes I, I sort of saw it. So part of it, it sounded like great fun.

Eva Amsen (32:06):
It's very inspirational to see people baking things. Um, is there any book that you have read recently that you would recommend to people?

Joachim Frank (32:20):
Oh, uh, well, the book by Ishiguro is probably very widely known now, so I really enjoyed it. And, uh, as, as you know, he, he got his Nobel Prize in Literature in 2017. So I, I got to know him.

Eva Amsen (32:36):
Oh, did you meet him in Sweden or?

Joachim Frank (32:39):
Yeah. Yeah. That, that was really fabulous. To see him there.

Eva Amsen (32:43):
And what about music? Do you listen to music?

Joachim Frank (32:48):
Yeah. Uh, I'm really, um, I'm very fond of classic music and, and we we've been to concerts very often you in, in New York City. Um, and then, but, but I'm very much a Reggae, uh, fan, uh, I mean, Reggae is, um, is so much on my mind that, uh, on for my 50th birthday, they, uh, they, um, did a surprise party, was Reggae, uh, on, on the Reggae and, and Jamaican theme.

Eva Amsen (33:26):
That's so funny. I, I love asking people this, if you were not a scientist, what do you think you would be? Any other career?

Joachim Frank (33:37):
Well, I, I would, I would really an artist and, and, and writer. Um, I think I never contemplated this kind of career because I thought it, it's not going to be, um, you know, only, only a few people really make it. And, and the other ones don't, don't really have a very, very good existence and be, besides this my, my father. Um, he, he had had a very, um, negative, um, attitude toward, toward artists. Um, he, he thought he, they were sort of parasitic on the society.

Eva Amsen (34:16):
Well, now you kind of have both careers in a way, cuz you managed to, to get your novels out. Um, we we're coming to the end of, um, our episode, but, and we, you already mentioned this earlier actually when we were talking, but my final question to you was, do you have any advice for researchers who are just starting out on there?

Joachim Frank (34:38):
Well, there's the thing about peripheral vision there. I already, um, uh, talked about, uh, there are things that coming up from the wayside and then you have to not treat them as, as uh, uh, disturbances, but better rather as opportunities to, uh, you know, look at at, at other things, you know, open yourself to, to other, uh, influences. Uh, and, uh, and then the other one is, um, that, uh, my personal experience with a mentorship in [inaudible] place was that, that I really, I developed ideas, uh, not under his guidance, but in opposition to his guidance, uh, there, so there were a number of things where I thought, um, I was confronted with opinions that I thought were, were untenable. And, and, and so, so I give him credit for this, uh, you know, in, in this environment, I, I, I was, um, I was able to be creative, uh, because of, of the things that I had to contend with, so, so the advice is then, uh, that if you have some, some really, uh, some ideas that, that you really believe very strongly and then, uh, don't let yourself be talked out of it. Yeah.

Eva Amsen (36:12):
That's good advice. Well, thank you very much, Dr. Frank, um, that brings us to the end of this episode and thank you everyone for listening to, or watching this very first episode of Cryo-Talk. Until next time.

Intro/Outro (36:30):
Thank you for listening to Cryo-Talk: a Bitesize Bio Podcast, sponsored by Thermo Fisher Scientific. To view all audio and video recording from this series, please visit Bitesizebio.com/cryotalk.