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Intro/Outro (00:00:03):
Welcome to The Microscopists, a Bitesize Bio podcast, hosted by Peter O'Toole, sponsored by Zeiss Microscopy. Today on The Microscopists - Hi, I'm Peter O'Toole and today, brilliantly, I got to speak to Scott Fraser of the University of Southern California about courses at Woods Hole.

Scott Fraser (00:00:31):
It was, it was the most exhausting summer I've ever spent and just the most enlightening.

Peter O'Toole (00:00:38):
Essential lab equipment.

Scott Fraser (00:00:41):
The first piece of equipment I bought at Caltech was a full restaurant sized cappuccino making machine.

Peter O'Toole (00:00:51):
And new recruits.

Scott Fraser (00:00:53):
These are the new kittens that are the addition to the family,

Peter O'Toole (00:01:00):
All this, in the episode of The Microscopists.

Peter O'Toole (00:01:10):
Hi, I'm Peter O'Toole and today I'm joined here with Scott Fraser from the University of Southern California, Scott hiya.

Scott Fraser (00:01:18):
Hi, very good to spend time with you.

Peter O'Toole (00:01:21):
Yeah, do you know, it's because of spending time with you in the past, that I really wanted to do this today. In fact, this whole idea of talking to different scientists came from my conversation with yourself, back in Dublin ELMI 2018 I think it was?

Scott Fraser (00:01:39):
Uh I think it was.

Peter O'Toole (00:01:41):
And actually, I think you, you you'd just come off the plane. I think I met you in the bar just to say hello briefly, you were eating. And then we had, we caught up after at coffee and I was intimidated a bit. I had to introduce you for a plenary session. I thought how do I do that? And actually I just got chatting with you and I thought actually your backstory off record is far, is probably more revealing about the personality and what made you so successful , I said. So this is why I thought it'd be great for others to hear these sort of stories as we go along. So I'm going to pitch in with you very quickly. Start, kick this off. What was your first experience? What was your first microscope that you used?

Scott Fraser (00:02:23):
My first microscope was at Johns Hopkins when I was a grad student and there was a Zeiss Universal in a closet in parts. And so I had to figure out which part went with which with no manual. And at, of course it was an older model, so it wasn't a state of the art in any way, but it was a great learning experience, pulling it together and and using it and figuring out everything for the Nomarski to the Baroque camera system that it had.

New Speaker (00:02:58):
So you are officially a closet microscopist at the start?

Scott Fraser (00:03:03):
Closet micrsocopist? The great thing about being in a department like the Hopkins biophysics department is there was a lot of skeletons and microscopes and electrodes and everything else you could imagine in the closets. And so half of my thesis involved finding those bits and pieces and assembling them into the equipment that I needed.

Peter O'Toole (00:03:26):
So I'm going to be guessing that you were biophysics, whose first interaction was in your PhD days, grad days. Were you ever, did you ever think you'd become a serious microscopist? Was that ever on your radar when you started your degree or anything else, or was microscopy something that you came upon through your studies?

Scott Fraser (00:03:44):
So I had been a physics student as an undergrad and spent a lot of my time building equipment, mostly to do measurements on lipid membranes. So bilayers and such. So my specialty had been developing sort of low noise electronics and deploying vibration control and all the other things. So I never thought at that point that the optics would be more than just a tool to help me get the light in there and get an image and make sure that the specimen was where I thought it was. And it was then when I was a grad student that I made the mistake of looking through a microscope and seeing an embryo. And it was a a moment, I don't know, I guess you call them epiphanies or whatever, but it's, it was phenomenal to see the cells develop to, to watch how after a microsurgery, the cells could heal in so quickly. And then every question I asked of the person that was showing me the embryo, the answer was, we don't know, and that seemed fantastic. And so that sort of got me to suddenly change fields. And it also got me to realize that I needed to use the microscope now as the way of interacting with my specimen rather than the electronics I'd used before.

Peter O'Toole (00:05:17):
Right. So that's that that's quite a change. So you went from physics to biophysics, so you weren't, you're not a trained biologist obviously. So how have you

Scott Fraser (00:05:31):
Yeah, many of my friends would say obviously,

Peter O'Toole (00:05:35):
Did I really just say that? Originally you weren't a biologist, so how did you, how did you find picking up a completely different science?

Scott Fraser (00:05:44):
So it was it was fascinating each of the transitions and those transitions are both terrifying and fun. I was a student at Johns Hopkins and started doing biophysics, as I mentioned it as an undergrad working on lipid membranes. And when I came to the Hopkins department, I, I thought I was going to work on membranes still and membrane transduction and things of that sort. I had the sudden change in the fall when I made the mistake of looking through a microscope. And I was lucky that the Woods Hole Embryology Course was that upcoming summer. And my PhD advisor had been asked to serve on the faculty there. So I applied and got into the course and it was being dropped into the deep end of the pool quite literally because I would ask questions and I would get answers.

Scott Fraser (00:06:56):
I remember the first time I was helping somebody with setting up a microscope, it was an old universal they had found in a closet at Woods Hole and we looked through and there's this beautiful specimen in Nomarski and it's rainbows, the colors and everything else. I said, that's spectacular. What is that? And and she turned to me and said, that's a pluteus. And the only answer, the only way you can answer that is, Oh! But I had no idea what a pluteus was. So I started doing my my reading for that course by having two or three other books open at the same time. This is a long pre-Google. So this was the the paper version of, of Google searches. So there was always a word in one book that didn't make sense. So I'd have to look at in the other book to try to, to make it all come together. I was very lucky there because the course just really the Woods Hole Embryology Course just really gives you an exposure indepth exposure to many different systems. And at that point Woods Hole was really a meeting ground for all the scientists in all the fields that I could imagine. And so it was a chance to be a disciple of many different people with really interesting backgrounds.

Peter O'Toole (00:08:27):
Yeah. I actually oddly relatively similar myself. I was a lipid protein interaction biochemist and through to biophysics. And actually I went on a course at EMBL and it was that course, with Rainer Pepperkok, Philipp Bastians and Timo Zimmermann, Jens, that really inspired me to, to carry on and to change my career attack and to move into the direction of the technology rather than studying the biology, which is obviously as a PhD from my side is in the biology department is all about the biology, but it was the technology that interested me most. And that's why I went forward as well. Those courses can be really inspirational.

Scott Fraser (00:09:10):
Oh yeah. It just, they just open up. It was the most exhausting summer I've ever spent and just the most enlightening and you know, many times people talk about these courses at EMBL or Woods Hole, or at Cold Spring Harbor as being really life changing moments. And they are,

Peter O'Toole (00:09:32):
You sent me some pictures in advance of this, and this is one of them. So I have no idea what this picture is off, by the way.

Scott Fraser (00:09:42):
Well, I think I recognize a former version of me. And this is just after we moved from UC Irvine to Caltech and it at UC Irvine, we had started building low light level microscopes to watch cell migrations and cell lineages, and to watch synaptic connections rearrange inside of live animals. We, at that point had a friend of a friend who serviced x-ray machines at the airport, and we were able to get them to sell us a a used SIP camera. It was dumb luck because the fact that it had been bombarded with the x-rays actually reduced the noise level and let us make some very simple electronics, because this is before it was easy to buy good frame grabbers and all. What you can't see in this picture is that there is a complete wall of of Nimbin computer parts up above that are doing the frame grabbing.

Scott Fraser (00:10:57):
You can see what was that called a Nuvicon and a SIP camera from Hamamatsu. This is after we'd moved us to Caltech. So we actually had some money and could buy real cameras. And that's when we discovered the lucky thing previously of having a SIP camera that was used that had a, a lower noise. And so this was our first setup. It's when we were making us image processing control or an image acquisition program, and then a processing program that we called Vidim for video imaging. And it was, it was it was a great time.

Peter O'Toole (00:11:44):
So you're obviously used to putting things like that together yourself, so how much of that is influenced by your your interests and I believe that you make your own amplifiers at home.

Scott Fraser (00:11:58):
Yeah. So it's very interesting the way that hobbies can end up influencing things. So I've, I've enjoyed building electronics and building devices for a long time. And I mentioned that my work as a undergrad was building very low noise electronics, and my goal was to make those very low noise, so they could make measurements and also very reliable. So when the one out of 10 experiments works, the equipment doesn't fail. So all those same sort of things matter if you want to sit down and listen to a stereo in a relaxing way. And so so some of the same practices that I've learned building electronics for the home to be reliable, I used them in the lab. And then when in the lab, when I figured out a way to beat down the noise or to increase the signal to noise, more notably, then I would apply that back to what I had built at home. And so it was a very fun virtuous cycle. We did that and yeah,

Peter O'Toole (00:13:11):
Yeah. I sorry I, go on. I know this is also a podcast, so I'll have to talk to people through this. But go on, can you show us some of your amplifiers?

Scott Fraser (00:13:22):
I can, but I, I you're, you're going to get motion sick if I show them to you.

Peter O'Toole (00:13:28):
Oh go for it.

Scott Fraser (00:13:28):
Okay. So so I'm here. One of them, that's a a tube amplifier behind that has the kitten proofing on it right now. Cause they're quad electrostatic speakers in front of it, for those of you who know old English companies that's the turntable like that's, that's the second turntable I built, that's sitting there that was built by a consortium of people that built different parts. And that's where some of my equipment building came in. So some of the vibration control that went into the motor pod and into the turntable platter is stuff that I'd done to beat down the low level of vibration so I could study, um so I could do imaging better. And so I could do lipid bilayers, which were very sensitive to vibrations better.

Peter O'Toole (00:14:29):
And that turntable? The base of it?

Scott Fraser (00:14:33):
The base of it is a very special wood that, that had to be collected in a there it's only available in Scandinavia in a store called Ikea, it's a cutting board. So, so part as you know, part of doing imaging and building equipment is finding things in the junk drawer that you can make work. And so what I needed was a piece of wood that was thick and relatively deadened. And and so rather than making one, I found the, the cutting board was just the right thing.

Peter O'Toole (00:15:14):
Um so the cage on the amps, was that to protect the amps or to protect your kittens?

Scott Fraser (00:15:21):
It was to protect the kittens. The kittens had been running around here. These are the new kittens that are the addition to the family. They came from a farm in Fresno, a friend was up visiting her brother. And so they are 11 weeks old almost. And some of the first things that had to happen is that I had to kitten proof things. You could see that the turntable already had a cover on it, but kittens and turntables like to amuse one another, the the tube amplifier actually, since it's off, I can show you.

Peter O'Toole (00:16:10):
That big cage structure is now off the amp and...

Scott Fraser (00:16:12):
The big cage structure is off. So those are 211 broadcast triodes. So that's a single ended triode amplifier. The cats, I took this off the kit, the tube cage and this is built a lot like the way that we put enclosures around microscopes. But when we do come closer to the microscopes, you don't want to have holes that let the dark leak out. Yeah. So but in this case I needed something that would let the heat out.

Scott Fraser (00:16:49):
So this enclosure hooks on to the top with with Velcro and those tubes, it's a, it's a very good way of heating the house and generating very nice music, but not very efficiently. I think the amplifier puts out about 12 or 15 amps, 12 or 15 Watts. So they're they're flea powered amplifiers some of mine are even 10 times less power than that.

Peter O'Toole (00:17:22):
Right. So that innovation at home and at work, and at home and at work, obviously from my own side, I think that I was obviously, I'm a lot younger, so I didn't know you before this point, but I do recall when the Meta came out I, I remember picking up the Meta information, reading the background and your name was all over it. Both in the Zeiss literature and otherwise, and the Meta, which I think was, was very disruptive to the market when it came out.

Peter O'Toole (00:17:58):
And it's still in existence today. And actually our users use the QUASAR, which essentially spectral head a lot now, especially on the latest additions with the sensitivity, but you were behind that if I'm correct?

Scott Fraser (00:18:12):
So, yeah, so the Meta was, was very fun because a lot of things developed through me complaining. So I guess I should explain that. But at Caltech there was the round table and the round table was at the university club where people would just go and sit down. And the person that sat next to you could be somebody from your department. It could be somebody from physics or astronomy, or you never know what it's going to be. So it's not unlike say high table that some of the colleges in the UK. So a great mixing ground. And so a lot of the innovations that we got involved in were the product of sort of chance interactions. So people saying what's new and even either they had just had a major success or they just had a major disaster. And both of those were were sort of engines of innovation because people would say, well, you know, I, I don't know, but, but in our field.

Scott Fraser (00:19:30):
And so I was sitting in that case with a couple of people from JPL that were in the remote sensing community, and I was describing this problem we were having with bleed through of different labels and they started ridiculing me because they said that when they flew a satellite over, they did not have a giant blue filter they could put in front of the sun so that the earth was only illuminated with blue light. So they could study the light that came back. So their approach was to to use the spectrometer and then to decompose that signal and be able to be able to you know, make the best of what they're getting back and make the beautiful maps that we've all seen in the beautiful photographs we've all seen. I have to rescue my power cord. My specialist assistants are in the room still and they are they are fascinated with the laptop power cord.

Scott Fraser (00:20:36):
Anyway. So, so the JPL folks knew how to deal with the signal that came back and the signal was never perfect and they made,utheir best,uyou know, images out of decomposing that image, of course, they had way, way, way more photons per pixel. So we then,utalked to some friends at,uJPL and we were able to get one of the spectral filters, the tuneable filters that,uwas being used,uon one of the Mars probes. Uthis was a spare. So we didn't,uransack it. We arranged to borrow it and installed it in one of the microscopes. And it was a voice activated,ufilter. We would take an image and then I would tell the postdoc to change the wavelength and then we'd change, we'd take another image. So those first, the first images to see if these decomposing approaches could work in the low signal to noise regime, that is optical microscopy happened with a group of us sitting in the dark and changing wavelengths and doing a band sequential collection.

Scott Fraser (00:21:55):
And of course that spectrometer was not built to be very light efficient for anything else, but its result showed that it could work. And what's always fun for me in building equipment is going from a complete failure to something that fails a little bit less. And once you know that it's going to fail a little bit less, once you've got even a taste of success, you can see what you could optimize. And so clearly a band sequential is not a great way to collect light efficiently. If you've got infinite amounts of light coming back off of the earth surface or something, or off of Mars, you can afford but we couldn't. So that's where the design for the Meta then came from, is we built a spectrometer and collected the photons as efficiently as we could.

Peter O'Toole (00:22:50):
I thank you.

Scott Fraser (00:22:54):
Well I should say that I think half of my career is taking advantage of situations that bring people that have problems and then have solutions into the same room. And so my first purchase, the first piece of equipment I bought a Caltech was a full restaurant size cappuccino making machine. And I got ridiculed by that until everybody and their dog started coming to my conference room to make a coffee and then sit down and they would either come just after something worked or just after something failed. So there must have been in that first year of that coffee machine, there was probably a dozen or two dozen patents filed just based on the fact that people would come in and they would either be elated or depressed, but they would talk to the other people that were there stealing coffee. So, so bringing things together, bringing people together and causing that sort of interaction is I think a real important way for us to to innovate. I mean, otherwise, you know, you can end coming up with the perfect mouse trap, but for a mouse that nobody has, or, you know, a, problem, a solution for a problem, nobody has. What's great about something like meeting up at the, at the cappuccino machine is you hear about the problem that's depressing them that moment. And if you've got a solution for it or think you could tailor it, it's a way to move forward,.

Peter O'Toole (00:24:36):
Which is really cool advice. And you hear it quite often as well. There's no point inventing something for the sake of it. Uh yeah, a way it's good to have a reason and a target and application at the end of it. So I read that literature in that brochure. I was envious and then several years later the Zeiss came out with their 880 Airyscan. And I was chuffed. This is where my head gets really big because I was the first beta test site out of, Jena, out of the factory and it came to York. I didn't know where it was going next. And then actually I think it came to you next and obviously Jan Ellenberg EMBL. And when the brochures released, my name was in there, I was so proud. And then you were there and I realized, wow, I was before Scott, I was before Jan and then it dawned on me. They only did that to make sure it was good enough to send to you and then onto Jan.

Scott Fraser (00:25:29):
I don't believe that at all. I don't believe that at all. I think one of the really fun things about interacting with companies is that they have to test things and make it robust enough that the the least capable user can still get good results from it. So if you build something around your lab, it could be much less user friendly. And so it's been great fun for me to work with companies in the molecular biology areas and in the microscopy areas to realize what it takes to go those extra yards, to make it robust. And so it's really fun watching the beta process happen because often companies are surprised by how creative people are in making the, the machine fail. So, so we, we had in fact, one of the co-inventors of the Meta was used by almost everybody in the lab eventually, to be the I don't know the stress test of any new machine.

Scott Fraser (00:26:46):
So we would troubleshoot, if we'd been certain that it could not fail, it could not crash. And then we'd say, well, okay, now it's ready for Rusty. And Rusty would come in and within 30 seconds he would have either frozen it, you know, smoke seldom came out of the machine, but yeah, but sometimes. So it's, it's a fun process to think about how to make these tools robust enough. And so you, I'm glad that you were lucky enough to be there as the first beta site, because I'm sure it was beautiful, but I'm sure it also had its growing pains.

Peter O'Toole (00:27:22):
It was pretty good actually out the box. I've got to say we did beta testing for the Zen software way back in 2005, 2006 of Zen. And that, that was, that was a lot rustier. And actually you're right. Actually what we had to do is try and get lots of different users because what you realize is everyone uses software differently. They don't conform to a nice, easy ritual because the microscope is so diverse. As soon as you enter it, you have to go, there isn't one root of buttons to press. They optimize in different ways. And the only way to find the bugs is to go through that sort of process itself.

Scott Fraser (00:27:57):
Right. Right.

Peter O'Toole (00:28:00):
So yeah, that, that, that one,

Scott Fraser (00:28:02):
It's great fun to be in to work with companies on that and watch as they take it from something that's a good idea and then figure out if there's something practical, something that you could afford to deploy and afford to sell. I mean, if people were willing to buy things for an infinite price, you could afford to develop a lot of new tools.

Peter O'Toole (00:28:25):
Yeah. So, think thinking about Zeiss, actually I, one of my most memorable moments of meeting you. It's another, it's another eating occasion. There's a lot of food in this. At least I think it was EMC 2012 and Zeiss actually took, took us out for dinner. So there was yourself Jeff Lichtman, Tony Wilson, and a load of the Zeiss individuals.

Scott Fraser (00:28:50):
Yes. Yes.

Peter O'Toole (00:28:51):
I remember turning up in an open neck collar, as I am now. You were also in open neck as was Tony and Jeff, but however, you all had, all had jackets on whereas I didn't and Zeiss were all booted and suited.

Scott Fraser (00:29:04):
We weren't from York.

Peter O'Toole (00:29:07):
Hardened northerner used to the cold weather.

Scott Fraser (00:29:13):
Yeah, right, you're used to the cold weather, the rest were softies. But anyway, okay.

Peter O'Toole (00:29:15):
I remember, I think it was either you or Tony who commented on the fact, Oh, have you not got a jacket? So I thought, Oh, okay. Yeah. Again, feeling a bit out of my league here in the company. And then at, to my recollection as well, we sat round and Zeiss all had their ties on. And at one point, I don't know. Do you remember this?

Scott Fraser (00:29:35):
Yes, but I don't remember what, what suddenly did it, if there was the the blessing of somebody that said you could take your ties off or just one of them did. I think it might've been Jim Sharp who started loosening his tie and that was like permission for all of them.

Peter O'Toole (00:29:51):
Yeah. They all, all of them. And there must have been what, 10 of them maybe? That all took their ties off simultaneously. It was, you know, at one point I thought I might've been in a striptease. It was so simultaneous.

Scott Fraser (00:30:07):
Well, one of those, one of those Full Monty moments,

Peter O'Toole (00:30:11):
No offense to them, but they do like a Full MontY type of crowd as well.

Scott Fraser (00:30:15):
Yeah. Yes. That, that, that would have been an even more memorable evening.

Peter O'Toole (00:30:21):
So that was really cool. So thinking of food, I'm going to ask you some really quick fire questions. Okay. So you got to choose one or the other so - eat in, eat out?

Scott Fraser (00:30:37):
Eat in.

Peter O'Toole (00:30:39):
Eat in. Cook or wash up?

Scott Fraser (00:30:42):
Cook.

Peter O'Toole (00:30:43):
Is that because your partner is no good at cooking?

Scott Fraser (00:30:45):
No, she's great at cooking, but I, I love cooking. I am the world's worst baker because I always, I bake the way the, or I cook the way that I build equipment. I'm always trying, okay. If I tried to change this, it'll get either better or worse. And doing that in baking, I've made several versions of pita bread that were not intended to be pita bread. Just things that don't come out. But I, I love cooking. I love pulling things together. And I also love learning from, from colleagues. So one of the great things about being at a place like Woods Hole, where I, you know, went for about 20 years, to then later be on the faculty is the, the recipe exchanges. So we would do big dinners for one another on the faculty, big dinners for the students. And it's just a great way to to get to chat to people and get to learn from them. And of course it's such a great mix of cultures and backgrounds and, and tastes and all that that it it's cooking is just the real sort of, it's a discovery field for me. So, so I, I love that and I'm, I'm probably not the world's best washing up person. So around the lab or in the kitchen. So that's may also influence it, yeah,

Peter O'Toole (00:32:24):
It's definitely what dishwashers a for anyway, go on, carry on. Tea or coffee?

Scott Fraser (00:32:29):
Ah coffee, almost always, but I love, I love good tea and so good tea like Puerh tea or, or, well, anyway, there's many different teas and that's another one that's great mixing of cultures,

Peter O'Toole (00:32:47):
Book or TV?

Scott Fraser (00:32:50):
TV now. I ah, I do so much reading that I, I used to read a huge amount more, but I just I think, A-TV has gotten a lot better and B I've gotten less patient with reading.

Peter O'Toole (00:33:08):
You have to be one of the worst at quick fire questions ever. I get long answers for every quick fire answer. Go on, what are you watching on TV at the moment?

Scott Fraser (00:33:20):
Um we are rewatching BoJack Horseman, which I don't know if you've ever seen, but it's a, it's a bizarre animated show in which characters are either animals or humans. There's one married couple that involves a human journalist who's married to a yellow Labrador named Mr. Peanut Butter. And so it's, it's it's, it's an interesting, and it has it's probably more human than most shows that have real humans in it. So that's, that's really a lot of fun.

Peter O'Toole (00:34:04):
Okay. So the next few questions..

Scott Fraser (00:34:06):
I also love old movies though. Old, old video old movies are, are spectacular. And so that's, that's the, the main thing that we enjoy.

Peter O'Toole (00:34:16):
I think lockdown has certainly enabled a lot more old movies to be watched certainly on TV, cause they've got to fill for what they can't film by filming live and stuff. So there's certainly been more on. Except my children just aren't really into anything that looks old, just doesn't have the same ambiance around it. There's a difference. Bike, walk or run?

Scott Fraser (00:34:43):
Walk.

Peter O'Toole (00:34:43):
Bike or car?

Scott Fraser (00:34:45):
Car.

Peter O'Toole (00:34:47):
I knew you'd say that. So I believe this picture is of you in your Tesla, is that correct?

Scott Fraser (00:34:56):
Yeah, I was, I was lucky enough to get one of the first Teslas that was sold to the general public. The.

Peter O'Toole (00:35:04):
You didn't have to test it though? You know what, it wasn't a beta test, no?

Scott Fraser (00:35:07):
Nope, no, no, no, it's definitely not a beta test. So it was the 2001 that came off the, the manufacturing line. And one of the trustees at Caltech was kind enough to help me get placed on the, on the waiting list. And at that point I, I loved fast cars. And so I guess I was on my third or fourth Porsche and and I, which I loved and they're, they're fast and they're fun, but they're also noisy and they're probably not the most energy efficient than the world. And the Tesla just had so many fun things about it. Including that it could out accelerate the,uthe Porsche. So I thought I was going to keep both. And within the first,utwo weeks I started arranging the, sale of the Porsche because I'd get into the Porsche and I would think it was broken.

Peter O'Toole (00:36:13):
So, so you've got a very swish, a very designer driven car, but I'm looking at your house behind and that also looks very designer driven. So tell us a little about the house.

Scott Fraser (00:36:28):
Yeah. So I, I like architecture and I like architects. So this is a house built by Rudolph Schindler, who is a Austrian architect who came to the US and work. His first jobs, were was sort of being the deputy architect of Frank Lloyd Wright for most of the projects built in Southern California. And he and Richard Neutra actually lived together and developed some things together since some of his early designs Neutra did the landscaping for cause he didn't have his his paperwork yet to be an official architect. So, so this was a house built by Rudolph Schindler for a composer and a radio personality. He had an unusual set of friends and so the unusual set of demands. So he needed a house where he could have musical performances.

Scott Fraser (00:37:41):
And so the living room has cork flooring and ceilings that are higher and canted. And, and Schindler is an artist about a stealing space. So Schindler makes buildings the way that cells are, the way that organisms do things, right. It's not there's, so the closet, I can show you over here. This, I don't know if you can see the closet?

Peter O'Toole (00:38:11):
Oh yeah.

Scott Fraser (00:38:11):
The closets are actually they look like they're about an inch deep, but they're not. And it's because the, they steal space out of the bathroom that's through the wall. In the, in the linen closets look like they're about that deep because they steal space from the next room over as well. So he puts the things together, taking advantage of virtual space in the same way that organs pack into a body. Right. And, and so it's a, it's a really fun house.

Scott Fraser (00:38:47):
So Jorge Rodriquez, the composer that it was built for, his friends included Salvador Dali, Ansel Adams and Picasso, and the whole sort of modern music scene around Los Angeles. And so it's, it's, it's great fun. There's almost a fellowship of Schindler owners and, and there's also almost a fellowship of people that like to work on and help work on the restoration. So as with any old house the woodwork in many of the places had been painted over instead of being the natural wood, like the windows behind me were all white. And so we got tradesmen that loved the restoring houses and helped us to strip off the paint. And it's, it's a, it's a fun adventure.

Peter O'Toole (00:39:43):
I think Scott, you are living my dream which is not the way it should be.

Scott Fraser (00:39:49):
Well, when you're midway through rebuilding to thing like this, dream is not the right term, nightmare is the right term, because there are many things that needed to get built and rebuilt. And of course, when you take anything, so we'd remove something and there could be a treasure behind it, like a Schindler used to come on to job sites and redraw plans on the walls. And so we found a couple of places where he had redesigned a part of the house cause the owner wanted some change. But it was written on the wall. That was the blueprint. So that's the good treasures. And you can imagine the other sort of treasures you could find behind that are old plumbing that that's past its prime and other things. So it's not the most low stress thing. It's like, it's like resubmitting a grant or worse.

Peter O'Toole (00:40:46):
Yeah. Don't compare to resubmitting a grant. Ah, quick question, what is your favourite microscope? I've got your favourite car, your favourite house. What's your favourite microscope?

Scott Fraser (00:40:59):
Oh, I, there is something I love about the old industrial microscopes that Zeiss used the build. And so my first interaction with the scope as we were talking about earlier, was the Zeiss Universal that was in bits and pieces. When I first started my lab, you could buy the different parts from the industrial house either I built some scopes from Nikon, some from from parts from Zeiss and especially from the industrial things, we used the Zeiss UEM, which was a universal optics, but it was built for the electronics industry. And it was the thing that we did most of our intercellular injections on. And most of our imaging on, because we could bolt together the different pieces. I love the elegance of the new scopes, just like I love the elegance of the Tesla.

Scott Fraser (00:41:58):
And I love the elegance of new sports cars, but my first Porsche was great because that's one that I think you could do all the repairs with maybe three tools and everything was clear how it was bolted in, and you could probably easily stand in in any of the places you needed to get to, to repair something. So so I love those old scopes. I was around Woods Hole when the Axicam app came out. And I don't know if you remember the Axicam app from Zeiss, but it was a giant, I think about a meter on the side in my mind's eye, it's even bigger, but I'm sure it wasn't even a meter, but it was an optical system that was designed so that you could take different parts and stack them in different ways and make an inverted scope by swapping the parts around. And so that was great fun too. So I miss those days of scopes that you could bolt and unbolt and change.

Peter O'Toole (00:42:59):
So that's your favorite microscope. Or microcopes, I guess. Sort of generally an era, a generation of microscopes. Tricky question now, what is your favorite publication that you've authored or been part of?

Scott Fraser (00:43:17):
Oh, I love papers that come out wrong. So so one of ours, we years ago, were imaging how optic nerve fibers found their targets in the brain. And it was just after some of the neurotrophic factors and neurotrophic factor receptors had been identified and we showed that they were there in the system and we all knew exactly what was going to happen, that there was going to be trophic factors that change the withdrawal of the cells of the neurites away from the target cells if we limited the amount of the neurotrophic factor. And so using our our imaging approach and we started doing all this low light imaging, so we could watch lineages as they diversified or watch fibers as they would connect. We perturbed the neurotrophic factor environment. We either blocked or added extra neurotrophic factor. And it's clear that the animal had not read our draft of the paper because it did exactly the opposite.

Scott Fraser (00:44:34):
So in the presence of the neurotrophic factor, the fibers branched profusely, and in the absence of it, they branched less. So it looked like it was not something that blocked the retraction, but, but fostered the, the arborization of the fibers in that region. So that, that was a Nature paper that was just a blast because it it came out you know, the opposite of the way we thought it was going to. Um similarly another Nature paper that was with Andrew Lumsden and Roger Keynes is one of my favorite because there we were labeling individual neuronal precursors, and then watching them diversify in the hindbrain of a of a chicken embryo. And again, we knew, we thought we knew how it was going to turn out because by that point we'd done the neural crest and the retina, and we found that the cells were very, very potent and what we found again, the, the cells had not bothered to read our, our draft. The cells ended up being largely identical in their cell pipes. And they also ended up obeying lineage restrictions, which we did think was going to happen at the, at the rhombomere boundaries on the hindbrain. Right. So, so for me, what you really fun about experiments, and what's really fun about microscopy is it lets you address what really does happen. And I love coming up with, with experiments where, where we get surprised, where we find out it's completely different than we thought it was.

Peter O'Toole (00:46:26):
Some of the images, so I've got another image up here.

New Speaker (00:46:30):
Ah, yeah. So, so yeah, so this is a rendering done by Seth Ruffins, who's just the spectacular of molecular biologist, developmental biologist, but, but also computer scientist. And he's worked with us for quite some time and now has his own position at USC in the Stem Cell Department. But when we moved to Caltech, we started doing a joint development of light microscopy in MRI microscopy. And so that is a quail embryo at older stages than we were doing the lineages of the, in the hindbrain and all, but that's taken by a microscopic MRI and that's a quail embryo still inside of its shell. And so we were able in a live quail and lives xenopus and other systems that were optically hostile, to image inside and watch as organs took shape and as embryos patterned.

Scott Fraser (00:47:35):
And then of course one of the real challenges. And I think it's a challenge that faces all of us right now is how do we present, you know, giga voxels of data in a way that's intuitive. And where Steph Ruffins was an artist, he he could make renderings that seemed intuitive, right? Obviously the, the, there's not a lot of shadows inside of a quail egg, but you can see ways that he used the shadowing and other things to really give it a three dimensionality. And in many of the different MRI microscopy things we were doing at the time with a colleague of mine, Russell Jacobs who's the real driving force of the MRI. We you know, we could really park ourselves inside and watch as structure took place. Watch as ears were built and as hearts were built and things of that sort,

Peter O'Toole (00:48:36):
A stunning picture, and it's interesting that, you know, MRI to light microscopy is quite a big step. There's very few that, that, that, that, that really cover that breadth of technologies. And you've obviously had a lot of interactions with MRI, still having a lot of interactions with MRIs. So your team, is it mostly light microscopists? Is it mostly cell biologists? MRI? What what's so what the composure of your team?

Scott Fraser (00:49:03):
So, yeah, I, as I mentioned earlier, I love trying to get disciplines to play well together. And I was very lucky. And, and when I was at UC Irvine the person that I shared a coffee pot with was Russell Jacobs who was developing microscopic MRI tools out of machines that were meant to do chemical and MR. And so he was making the little MRI coils that would be in a normal human size MRI, but down to the size of say a frog embryo or a, or a quail or things of that sort. And this is where the lesson about the coffee machine came because every day we would come from opposite ends of the building, to the shared coffee pot and stay on there and, and either celebrate or commiserate and then we'd go back away. And so when I moved to Caltech, Russ came along and he headed a part of the lab that did MRI.

Scott Fraser (00:50:11):
And we were able to bring in Thomas Meade, who was a really gifted chemist and he headed up a probe development effort in the lab. And so what we tried to do is make agents that could sort of act as the Rosetta Stone. So we made a genetically encoded or chemicals that would allow us to do genetically encoded labeling with MRI. We made a lot of bifunctional agents that we could see in the fluorescence microscope or the confocal microscope, and then also see in the MRI and you're right, that there was a real void MRI is sort of a technique where the individual voxels are a millimeter, maybe even larger than that. Light microscopy at a millimeter you're no longer have very many ballistic photons and so it's like a huge gap. And so part of why we started building better and better two photon microscopes and trying to make you know, cause we saw that as one of the sort of frontiers we need to deal with.

Scott Fraser (00:51:16):
But it was to get closer to the MRI, the MRI we were trying to make it a higher and higher resolution. So finally Russ got the MRI down to about a few microns on a side of the voxel. And we were then able to look inside and see things inside of frog embryos that were just invisible by light microscopy because of the light scattering of the cells. So we never got it to where they overlap tremendously, but they, they did sort of contact one another. And and we were able to do some bifunctional agents that were really pretty powerful.

Peter O'Toole (00:51:59):
I mean, should say, you hadn't, you didn't quite get there yet. I think about,

Scott Fraser (00:52:03):
Oh, so that's, that's the goal now. So is how do we, how do we make it so that these technologies meet one another? And you know, we're trying to do that with the help now of some machine learning and other sort of tools of of dealing with either ultra fast imaging or ultra low signal imaging or signals that have very low amount of light going through. So, so really trying to redefine the, the impossible, I guess. Right now, you know, if anything that we say in the lab, if I want to try to get somebody to work on it, the way I do it, as I say, Oh, no, that's impossible. And you know, nothing motivates people more than proving me wrong in the lab. And so, so that's, that's a great motivating tool. The other great motivating tool is that most of the people in the lab when they leave, take their project with them. So there's oodles of projects that we loved and really enjoyed, but as the people left the project with, with them, so we all were always had to find something new that was impossible to play with. And so so we've, you know, I mentioned the retina terminal arbors earlier, there's postdocs that went off and made that into their, their career rather than us continuing on it.

Peter O'Toole (00:53:32):
That makes it sound like your team are inspired and, and admire you, but you also sent me, I've got these pictures where I'm sure this cardboard cutout is one of your lab begging you? Maybe?

Scott Fraser (00:53:47):
Yes. You definitely do not want to to be in an imaging lab if, if you don't like to laugh at yourself. So that's a cutout. Yeah. Okay. Yeah. That's good

Peter O'Toole (00:54:02):
Being shot at?

Scott Fraser (00:54:03):
Yeah. That's a, that's a physics student shooting me. Yeah.

Peter O'Toole (00:54:10):
This one?

Scott Fraser (00:54:10):
Yeah. I'm not sure what's happening there, but I don't think it's very good. That's a very great grad student, but he was, he was getting near finishing and I think he, his emotions may be showing

Peter O'Toole (00:54:22):
Yeah, that face in that, that, that a boa? Is it a feather boa around your neck?

Scott Fraser (00:54:29):
Oh yeah, yeah. Oh yeah.

Peter O'Toole (00:54:33):
And finally, this looks a lot like being chucked off a building?

Scott Fraser (00:54:38):
Yes. That student, I think has two different things in the video they made for my birthday. So they, they made this ah cutout of me at one of the grad students parties for their PhD. And then they took this kind of all over town to places that have mechanical bulls. I think it tried to break into a jewelry store several other things, but this, it was dropped off the building, its head was cut off. It was ah multipurpose. So imaging tools can, can really be used in creative ways.

Peter O'Toole (00:55:13):
Yeah. I can see that had just how much they really love you.

Scott Fraser (00:55:17):
Oh yeah.

Peter O'Toole (00:55:22):
I just changed changing, tack all together. This is you, isn't it? What is it you're holding?

Scott Fraser (00:55:28):
I am holding a wombat. So I love traveling and I think I sent you this picture because I, I was looking through a folder of one of my old assistants pictures from the lab. That's where the, the cutout pictures were. So this is when I was traveling to a meeting in Australia. And afterwards I went to one of the nearby zoos and it was a very slow day in the zoo. And so I was invited into the koala enclosure and got to go and communicate with the, with the koalas and in ways that would never happen in normal zoos. I was walking by and the person working with the wombat sort of, you know, said, do you want to come and hold the wombat? And there's only one answer to that question. After holding the koala, it seemed appropriate. That's so it's great to go traveling. It's great to go to meetings and it's just amazing what you can learn and what you can find while out walking in the countryside or through a deserted zoo or a wildlife park, I guess this was.

Peter O'Toole (00:56:52):
Everything so far, has sounded brilliant, but no career goes without it's challenges. So I've got just a few minutes left. What have been some of the greatest challenges that you've had to encounter? How'd you work? What was the most difficult time of your career and how did you overcome that?

Scott Fraser (00:57:12):
There, there are many, luckily there's been no major, horrible times in the career, but it, it, it is very ironic. You mentioned the Meta before. So we had the prototype of the Meta that we had built. Then we had the prototype that Zeiss had built. And then I wrote a shared equipment grant at Caltech to buy one and the study section questioned whether we needed one. And so that, that might've been a career low point to have the scope that you helped give birth to be viewed as something beyond your capabilities to use

Peter O'Toole (00:57:59):
Next time you need to write into that contract with Zeiss when you do something like that, that you need to, part of that deal is that you get the first system as part of it.

Scott Fraser (00:58:07):
Yeah. So, so in fact, we did end up getting a system from, from Zeiss and when we were involved in doing the 5 LIVE, we did the same thing. So we ended up with the 5 LIVE and in the lab as well. So yeah, so we've learned. The other hard things, I guess, is that it's different than in Europe, but, but grants in the US, grant proposals in the US often get listed as overly ambitious, if you're proposing to do anything you haven't already done. And so one of the frustrating things is trying to write up grants, the grant proposals on work that's sounds less venturous than, than what you're really going to do, because that's what you can manage to have the study sections approved. I've always wanted to do a compilation of the things that were impossible according to the study section, but then ended up being very nice Science or Nature papers. And I think probably every one of them we had ah such a review. So that's always fun. With any, with any scientists, there's always the dread reviewer three. And so the dark times happen, it can happen often, but not sort of, but at least with papers, you get the chance to argue back than in grant proposals, it's not as easy.

Peter O'Toole (00:59:41):
Okay. So I, I, I, because actually, I think the UK certainly has been very encouraging of blue sky thinking and go for very high risk. They encourage in some of the technical technology calls to be very high risk. They don't want something that's going to, what they want it, cause high risk is generally much higher impact. And I, I I'll come to it in a minute cause I remember one referee's comments coming back on a grant that was successful was really negative, but how do you rebut? You got maybe two glorious, excellent, outstanding, internationally successful type, this will be great, reviews, and then you've got one there's two problems. One is damning really doesn't like it at all and criticizes at every angle. And the other one, which is, yeah, it's okay, this is fine, which is done by faint praise and much harder to get that quick, very quick. How would do you rebut those two situations diplomatically?

Scott Fraser (01:00:39):
Well, what I, what I love is it, if somebody goes completely nonlinear and it actually sometimes helps. So we, we got a Transformative RO1 grant because a lot of the reviews said this would be spectacular. And then the other review said, these people are insane. And luckily the funding agency said, well, this is just the right sort of thing. If half the people think it'd be great if it worked and the other things think it's impossible. So, so pointing out that is great. I think the hardest thing is dealing with the damning with faint praise and the one that we finally talked a way around with a resubmission, but was hard as somebody said that the impact of the work that this postdoc was proposing would be about the same as adding one more digit to PI. And which I did not take as high praise nor did the programme officer. So needless to say we did not get that a postdoctoral fellowship funded. So I was think damning with faint praise is the hard thing, the, Oh, it's it's it's I guess in the UK, you'd say it's quite good.

Peter O'Toole (01:02:02):
Yep. But if that last digit of PI was the last number and it wasn't, you'd just solved PI forever. See then, you could've flipped it shouldn't you?

Scott Fraser (01:02:12):
We could have made PI into a rational number that would have just been amazing. Yeah.

Peter O'Toole (01:02:17):
Should I come back at that?

Scott Fraser (01:02:20):
Yeah. I should have called you up and you could have written the rebuttal for me.

Peter O'Toole (01:02:27):
Rebuttals are okay. Writing, I need to be in the right frame of mind to write. I can't just write, I can write rubbish really well, but to write things really well,

Scott Fraser (01:02:37):
I've read your papers. I would agree.

Peter O'Toole (01:02:42):
Cheers Scott!

Scott Fraser (01:02:42):
Sorry. I have an evil sense of humor, so I I've liked your papers, so I don't mean to break it up.

Peter O'Toole (01:02:51):
That's why I get others to write my workup, it's much easier.

Scott Fraser (01:02:54):
Ah,

Peter O'Toole (01:02:56):
You've just damned my whole team and all my past members. Thanks!

Scott Fraser (01:03:00):
Oh, okay, you're welcome.

Peter O'Toole (01:03:03):
Uh before we finish have you got any good, any advice for anyone starting out in their career? Cause you are where you are now. At the start, is that where you thought you'd be?

Scott Fraser (01:03:16):
In so many ways it is because when I started, I wanted it to remain fun and remain innovative. And one of the things that I just love is that being in science is like a fountain of youth. You're always interacting with the next bright-eyed grad student or postdoc or research scientist and and always trying to do something new. So that's, that's exactly where I hoped to be. I think though that my word of advice would be, always listen to words of advice and then ignore most of them because the nobody's experience is going to be completely relevant. So I'm always, when, when assistant professors come to me and they they've got a steering committee, that's given them advice that they don't want to take, I, I always try to mentor them to say, well, listen to it, try to understand what they're saying and why. And then do what it is you want to do. So I think that there's something very valuable in listening carefully and then selectively attending to which of those things you want to learn.

Peter O'Toole (01:04:35):
And you just said that to all your team that will watch this back and they'll now know whatever you tell them to do, they can completely ignore it.

Scott Fraser (01:04:43):
They do. So one of the best things about teaching at Woods Hole is I would leave for two or three months to go to Woods Hole and, you know, the opposite side of the country. They would work 10 times harder than they ever worked when I was in town to prove that I was not needed. So my job when I returned was to have to act very, very disappointed that they'd had amazing new insights while I was gone. Cause they, you know, that's just horrible. I mean the lab move forward without me. So, so it, it is very interesting. And I think that that the number of, of innovations that have happened around labs around the world, by students that ignored what their committee told them or what their mentor told them. Well, there's, there's a lot of them and I think there's a lot of lessons in that too, to listen carefully, but then selectively ignore.

Peter O'Toole (01:05:41):
Scott say, so you inspire by absence? Uh I would also say that you've inspired in your past and it's thanks to you that actually inspired these meetings that I'm having now. So Scott, thank you very, very much. You've been brilliant to catch up with as always.

Scott Fraser (01:05:58):
Thank you. It's great to catch up with you and I hope this isn't our only chance to catch up. And my hope is as things move forward that we'll have other things to chat about. If only we had a cappuccino machine halfway in between our labs,

Peter O'Toole (01:06:13):
I have, I've got the espresso.

Scott Fraser (01:06:16):
Oh, okay. That's close. I didn't see if you had people bringing them in during the meeting, but anyway,

Peter O'Toole (01:06:23):
Well, it's a cold espresso now. There's only a bit left.

Scott Fraser (01:06:25):
Oh, okay. Okay. Well thanks so much.

Peter O'Toole (01:06:29):
Pleasure Scott. And I look forward to trying one of your cappuccinos. Brilliant.

Scott Fraser (01:06:32):
Okay, that'll be great. Bye bye.

Intro/Outro (01:06:37):
Thank you for listening to The Microscopists, a Bitesize Bio podcast, sponsored by Zeiss Microscopy. To view all audio and video recordings from this series, please visit Bitesizebio.com/the-microscopists.