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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.

Tony Wilson (00:00:18):
But, of course, you have to understand in this part of the world, it's not a matter of how many cows you have per acre. It's how many acres you have per cow. So not quite, but pretty close to that, I'm afraid.

Peter O'Toole (00:00:31):
So size definitely matters. And I guess that your whole career is about being, making things bigger.

Tony Wilson (00:00:35):
Making small things bigger things. That's right.

Peter O'Toole (00:00:43):
Welcome to The Microscopists. In today's episode, I stepped into a brief history of how the confocal microscopy came to be with one of its pioneers, Tony Wilson, from the University of Oxford. Wearing his cowboy hat and boots throughout most of the interview. Tony talked about his passion for cattle his Jaguar and Yorkshire cricket, and how finding life scientists to this new technique was not as simple as you may know, think.

Peter O'Toole (00:01:16):
Hello? I'm Peter O'Toole and today in The Microscopists, I'm joined with Tony Wilson. Hi Tony.

Tony Wilson (00:01:24):
Hi Peter.

Peter O'Toole (00:01:24):
Yeah. I don't know if you, if you remember even, but actually the very first contact I had, obviously I knew who you were, but the very first contact I had with you is a letter through the post inviting me to be a member of the Light Microscopy Section at the Royal Microscopical Society. If we weren't still being locked down, I still have it in my office. That letter.

Tony Wilson (00:01:46):
Good grief. That's a long time ago, Pete, that, that must be 20 years ago. No less. No, it must be.

Peter O'Toole (00:01:54):
Definitely less. Yeah, totally.

Tony Wilson (00:01:58):
Sadly. I have white hair. Yeah.

Peter O'Toole (00:02:03):
So do I, if I go sideways. I'll be, I'll be sat here a lot today looking like that. So just to, just to hide that silver sheen within it, and I remember my first meeting and meeting you not, I wasn't nearly as confident I was feeling a bit, out of water really when I came in and you made it really welcoming at the time.

Tony Wilson (00:02:25):
It's very kind of you to say so .

Peter O'Toole (00:02:28):
Obviously I knew of you, your reputation proceeds you, obviously as one of the pioneers of the confocal microscope and we'll come to that in a little bit, but I quickly found out you're not all that serious. I saw him pointed out. He goes, Oh yeah, just get Tony, ask it to talking about Cowboys and I thought, what is this about, so Tony, I do believe that you're quite fond of your, certainly your cowboy boots,

Tony Wilson (00:02:56):
My cowboy boots, I'm afraid you can't see because of where, well, actually you can sort of see in that,uI took the precaution of having one here for you to see, but I'm not actually wearing it, but you can see the,uthe heel and the echt part of the cowboy boots. And I guess I have to complete the,uthe whole thing with the hat. UI, but it's a bit more than just the sort of,uurban cowboy. I'm actually quite interested in the cattle industry. And I'm actually speaking to you from Texas,uwhere I am stuck in the lockdown. And,uI got interested in this basically because of my father-in-law and,uwe have a place a few, well, it's about a hundred miles to the south of here,unear a place called,uWaco where we raise,uSanta Gertrudis cattle. Uand that say cattle breed that was pretty much invented in Texas for Texas at a thing called the King Ranch.

Tony Wilson (00:04:07):
And it's a cross, which is hopefully able to survive the Texas high summers which are pretty hot. And certainly in the south where the King Ranch is unlike here, it's very humid, but you know, temperatures of a 100 old fashioned Fahrenheit degrees are not uncommon for quite a long time. And these animals

Peter O'Toole (00:04:35):
Tony, that's a 100 degrees Fahrenheit? Yes?

New Speaker (00:04:37):
Fahrenheit old money. Yeah. Hot 30 odd in your money. And that's pretty unpleasant. The King Ranch in ventured, this breed and we have a whole bunch of them, the King Ranch, I might say by way of just illustration that in Texas people will like things to be big. I mean, there's the unfortunate joke of the person from Alaska who said, you know, if we chopped Alaska in half, you'd be the third largest state, which is true, but slightly unkind. The King Ranch, however, the height of its properties was huge in area and actually the King Ranch properties if you include the properties in Australia where the Santa Gertrudis, is a big breed. If you include that, then the King Ranch was larger in area, privately owned, I might say than the state of Rhode Island. So it's big.

Peter O'Toole (00:05:42):
It sounds, yeah, incomprehensibly big, actually, it's quite hard to get your head around in the size that we're talking about it,

Tony Wilson (00:05:48):
But you, of course, you have, have to understand in this part of the world, it's not a matter of how many cows you have per acre. It's how many acres you have the cow, not quite, but pretty close to that. I'm afraid.

Peter O'Toole (00:06:01):
So a size definitely matters. And I guess that your whole career is about being, making things bigger.

Tony Wilson (00:06:08):
Making small things, making small things bigger, that's right, exactly so, exactly so.

Peter O'Toole (00:06:14):
So just thinking about on your impacts, certainly the world of biology have been profound and many Nobel laureates have any been able to get to that position, thanks to the emergence and development of confocal microscopy for which you were very much behind the development and commercialization of that. How did that all start? It started by

Tony Wilson (00:06:40):
It started by accident and it also started by going up the wrong path and it's probably worth pointing out why we went up the, the wrong path. This is going back to the early 1970s and the thought actually a thought not had by me, but a thought had by a brilliant man called Rudy Kompfner who was an Austrian man who actually was an Austrian. He ended up in the UK during the war. He was a radiometer. He was actually an architect by profession and he ended up in the UK. And as I say, he was a radiometer and he invented on his own volition, a thing which became known as the travelling wave tube. And this was a way in which you could amplify microwaves. He turned out to be the, the key thing that made radar work as I understand it and the story that I heard was that he had this idea and he wrote it up and being an amateur, he sent the thing to a magazine called Wireless World, which at that stage and indeed when I was a child.

Tony Wilson (00:07:55):
Maybe even now, for all I know you could buy in newsagents. And the impressive part of the story is that someone at Wireless World realized this was a very good idea. And not only that, but they couldn't publish it. So he was, yanked out of internment, I think shipped off to Birmingham University to work with either Randlell or Boot. I can't remember who the inventor of the Klystron and the traveling wave tube became very important. He ended up in Bell Labs after the war. And when he retired from Bell Labs, he took two jobs, being a clever man. He decided to spend the English winters in California in Stanford and the English summers in Oxford. And the work that he set up in Stanford was the scanning acoustic microscope taking the view that actually all the optical microscope can do is look at variations in refractive index.

Tony Wilson (00:09:03):
And frankly, who cares about refractive index, whereas the acoustics like that these days, I mean, this was 30 years ago, a bit more. And so he thought quite rightly that the acoustic microscope, which really gives contrast because of the stiffness, the strength, the mechanical properties of the material, it will be much more interesting. He was writing that, but of course the acoustic microscope never really took off. In Oxford, We were doing the optical microscope. What we were trying to do the idea was, that most biological tissue is pretty much transparent. At that time we didn't really know why you guys use fluorescent labels. And we thought, it was and we were wrong, we thought it was because there wasn't enough contrast in the regular microscope image. So the idea was, why can't you do good contrast? Well, the reason is because you're trying to do it optically and optically.

Tony Wilson (00:10:14):
If you have a big signal with a small background, it's very hard to see the small background. There are techniques, but it's hard. In electronics, if you've got a small signal on a weak background, it's trivially easy to get rid of the large background and amplify up the small wiggles. So in order to do that, you need the signal to be an electronic signal. Now, remembering those far gone days, there were no such things as CCD cameras. So we had to somehow get the image electronically. Remember also back in 1970s, the laser had just about become a commercial viability, not the kind of things we have now, but you could get lasers at a reasonable price, pretty much the helium neon laser. And so we had a bright light bulb. And so the idea was to build on earlier work of the flying spot microscope, where the flying spot was actually a television screen that was de. So if the spot would scan across the TV screen, you would demagnify it onto the specimen. That will be your flying spot illumination. And you would have a photomultiplier tube to pick up the scan signal. So we had a laser, which we scanned across the specimen, and then we had a photomultiplier tube, and we built up the image point by point, as we scanned across the image on a long persistence television screen. So there was no capture,

Peter O'Toole (00:11:56):
If we hadn't got photomultiplier tubes it, go back one. If we had CCDs, when you started off would you even thought of going to the point source and PMTs or would you gone to try using wide film CCDs?

Tony Wilson (00:12:11):
So I suppose. Actually, that's a very good question because we started off once we'd built the thing, of course we have, I have this, I can't quite think of the word, but a wish to write down a mathematical model and the mathematical model is actually, it's sort of easier if it's scanning. Although I have to say, if it's scanning with a large detector, it's exactly the same mathematics as the regular wide field microscope, but you sort of think differently in the scanning thing. You think about the source and the detector in a way that you might not think about it in the regular microscope. So mathematically, without getting very boring, you start off with a source that you propagate the light through the specimen, to the detector. And if the detector is big without going into too much boring stuff, you have to do an integral over the whole of the optical intensity that arrives at the detector.

Tony Wilson (00:13:27):
And again, integrals are hard work. If you stick a pinhole, a point at the detector, you don't have to do the integral. Now, when we started off building these things, we knew nothing about optics. So we thought, how can we build a simple system? And we thought it will be easier because we didn't know much about optics. We felt fairly confident. We could take a spot of light and focus it to a point that after all is what objectives are supposed to do. And then we could have the objective re imaged that point onto the specimen. That way we thought the objects would behave well, that involved us having to scan the specimen in order to get the holes object. And that thing behind you is the very first specimen scanning stage. Thank you, that we built it didn't last very long.

Tony Wilson (00:14:30):
How did it work? There are two loud speaker coils behind you. Voice coils, which push the thing marked flexible legs. And the idea was that the specimen would sit on that stage. The voice coils would push like this and the specimen would scan and this scanner, which was actually designed by this man, Rudy Kompfner about his drawing. This lasted a few minutes, maybe 10, because of a thing we then learned called metal fatigue. So this thing fell to pieces and we had to build a better one. This worked, I might say remarkably well, but of course was not convenient for imaging any specimen, which was not pretty small. It also. And we also scanned the thing vertically, which for biology biology, by the way, doesn't seem to work vertically. Biology wants to be nice and flat and calm. And I don't blame it. I like to be nice and flat and calm too. So we, we then moved on to a stage scanner that was horizontal. Then it became obvious when we'd learn a bit more optics. Well, actually you really do have to scan the beam. Obviously you do

Peter O'Toole (00:15:57):
For, from that stage, you've got the basic sort of confocal microscope. You see the potential and there's huge potential. Obviously we know what its potential is now. We realized that that potential or to a great degree, how easy was it to take the idea? You've got a scanning microscope that works, how easy was it to get a biologist to actually use it and to, to become widely accepted as it is today?

Tony Wilson (00:16:24):
It was hard. And I don't blame the biologist. Also, we had one, I had a very good friend in Oxford. Tom Kunene, who was a person who loved technology the com he really did. And the system that we had didn't , wasn't conducive to biology. I mean, one trivial way. In Oxford where this was going on, there is a science area where all the departments are pretty close to each other. In reality, the engineering science department, isn't actually in the science area, it's pretty close. It's a two, three, four, five minute walk, but it involves a four or five minute walk and it involves crossing a road and biologists didn't like crossing the road and biology in particular, didn't like crossing the road still didn't until the last few years, when we started doing experiments with C. Elegans. And so on, finally, we got those things to cross the road, and I might say talking about biology, wanting to be, be nice and calm. These C. Elegans came and the donor of these things they'd look at them in this Petri dish, they are grazing on a lawn of bacteria. Well, my goodness grazing on a lawn of bacteria across Parks Road was not an easy thing. And so it was hard for them to get the biology to us. Our stage scanner, wasn't conducive to biology, if I'm completely honest, although later on, we were able to do what I think was really quite remarkable things with the stage gunner, but it was fighting the technology. It was also new, which meant to say it didn't work every time.

Tony Wilson (00:18:25):
It was also new right at the beginning before the image capture software in that we had a long persistence television screen. So the scanning wasn't fast, the scanning wasn't real time. You had to turn the lights out in the lab. So it was a relatively painful way to get the specimen. And I really don't blame the biologist for not cottoning onto what we were trying to do because it was hard. And the, the biologist, perfectly reasonably, their main interest was biology. And we couldn't provide them with the wow image or the ability to see biological processes or to see cell division to watch it happening, to do 3-D reconstruction, because we weren't at that stage yet.

Peter O'Toole (00:19:22):
I think it's quite frustrating to, to know what you can do in the technology is still needing to be developed. The ideas there it's done. It's actually develop it into something that it becomes functional to a biologists it's useful to them. That must be quite a tall order.

Tony Wilson (00:19:39):
It's a tall order and you, you do it in stages. And we've been incredibly lucky that parallel technologies have developed along with the confocal. I don't think we could have actually built a better system. Even if we'd had Janelia Farm type funding in 1970s, then we did. The lasers weren't there, the image capture, wasn't there image processing wasn't there, so that couldn't have happened. So I think we did what we could. And also to be honest, we were starting off. We were aiming, aiming it at the semiconductor industry because what, what were we actually doing? If you, if you strip out the application, we were adding a third dimension of resolution to the optical microscope. The optical microscope can do nevermind arguing, it can do well in X and Y it can measure dimensions in X and Y it's hopeless in Z. It's hopeless measuring dimensions.

Tony Wilson (00:20:51):
I mean, I'm waving hands in, in this it's hopeless in Z. So what we were trying to do was to introduce resolution in the Z direction. So you could then measure things at X, Y, and Z. You could measure volume for instance. And so the idea was we could do critical dimension metrology, which in the semiconductor industry X and Y are critical. Z is even, is equally critical. If Z is not right, the device won't work. So it was adding extra functionality to the conventional microscope to provide this Z resolution. Did we, as simple engineering scientists know anything about biology? No. Did we realize that you could see these,uprocesses as the cell underwent mytosis? We'd never heard of the word? Mytosis, of course we didn't know.

Peter O'Toole (00:21:54):
And I, I think you're right. I think the biologist wasn't demanding this either, cause I don't think because it wasn't available, they weren't needing it. So you've also got an, an untapped market. So it's not until they become aware of what it's capable of do suddenly they want everything, if you ask people now they want even more and more and more, of course, really snowball. Now they got past the first hurdle, which was the confocal really pushed them on. Oh wait, just take you back a bit now. Right? From the start you've made this massive impact. Where did you start though? What, what was your undergraduate in to start with?

Tony Wilson (00:22:30):
My undergraduate degree was in Oxford, in engineering science. And that I think was a very, very good foundation then. And it was a course where you, you had options, you had options in the final year and they were options of a kind that no one has these days. There is. So in year one and year two, you had no choice whatsoever. You did everything in year three, you did everything for, I honestly can't remember. Let's say for half the year. I really don't remember. And then if you wished you could take an optional paper and I, I, again, I don't remember, but mostly it was engineering science list. Just make it up and say, you could take an optional paper in electrical subjects, mechanical subjects, civil subjects, fluid dynamics, thermodynamics. Can't remember that was. Oh, that was probably it. And you could do an optional project if you so wished.

Tony Wilson (00:23:38):
And then you could submit this optional project as part of your final marks and you could do the same thing with the optional paper, but it was optional, which meant you could do it or not. As you wished, if you didn't do it, that was fine. If you did the optional paper and you did badly, it was ignored if you did well, it took, it took it, it helped. So you had nothing to lose, nothing to lose. So what it meant was you learned a lot, actually about a lot. So I think that led me, that helped tremendously because one of the things as I said, we had this voice coil, this loud speaker to do the scanning, but we had the background. So we actually sat down and said, well, can't we design a better loudspeaker. It's an electromechanical device. We know all about MMS.

Tony Wilson (00:24:44):
We know all about Ampere's law. Surely we could build for our purposes, the whole thing, and we can build a scanner into it as well. So we can have electromagnetic coils. The thing which normally the thing going in and out would actually have the specimen on it. We could have two or four of these magnetic circuits and we could control the scanner. We could scan it in X and Y we could scan it in [inaudible] figure we could do all of these things, which if we hadn't had this broad background, I don't think we'd have come anywhere near

Peter O'Toole (00:25:21):
Right. So I'm noticing the book in your background actually, which I think says electricity and magnetism. So tell me that doesn't date back to that, that time.

Tony Wilson (00:25:30):
Yeah. The book does that version does not.

Peter O'Toole (00:25:35):
So what, what, what followed after that? Cause you know, for your microscopy, I bet you at, through your undergraduate, I bet you didn't even think about a microscope.

Tony Wilson (00:25:45):
Didn't think about it at all. I mean, I started off my PhD or other DPhil if I'm, if I give the Oxford words, working on the subject of integrated optics, the whole idea of being optical fibers were beginning to be the way forward in optical communications. And the whole idea of optical signal processing was important. And one of the ways that you could do that was via this technique of integrated optics, where the optical signal would travel along an optical wave guide in an optical circuit, you would have various filters or switches couplers that you would build into this optical substrate. These were electro optic materials and you could switch light to go in one direction or the other, that was what I started off working on. And that was very much flavor of the month around the world. But we didn't have the, or we didn't, my supervisor didn't have the funding for that.

Tony Wilson (00:26:59):
At that time, this chap Rudy Kompfner was a visitor in the department. As I said, he spent the summers in Oxford. Pretty much by the time it became clear this initial project was not going to be able to lead anywhere because we couldn't do any experiments, was let us imagine around Easter, which was around the time he was floating through. And I got interested in what he had to offer. And so I switched projects at about Easter of my first year and worked on this for some time then got interested in some other bits of nonlinear optics and played about with that for a bit, then spent some time in Bell Labs in the United States where I worked on buying a stable liquid crystal displays, the idea being you, right, whatever it is you're interested in, in the display to turn off the signal and the things that he's written, the Bell were, obviously interested in that for the phone systems.

Peter O'Toole (00:28:16):
So when you, that's quite a big switch, you're in Oxford for quite some years, and then you switched over to it. So how did you find moving over to America and.

Tony Wilson (00:28:26):
Bell Labs at that time was coming towards the end of being the great Bell Labs that's to say, it was the time of the antitrust suit, which in the end ended up with Judge Green, splitting up the well, just very quickly AT and the Bell Labs was partly owned by, AT&T and partly owned by Western electric. The problem being AT&T owned both Western Electric and the Bell operating and companies but being in Bell Labs was fantastic. The people there were incredibly good. Remember this was quite a long time ago. And if you wanted a paper to read, you just picked up the telephone, spoke to a tape recorder the next morning or shortly thereafter, a photocopy was on your desk. It was the only time where the mantra 'spend money to save time' was the way you did. I mean, right now in a university, you wouldn't dream it, but you would dream of it possibly but wouldn't do it.

Tony Wilson (00:29:42):
So that was that was a real eye opener, but by the way, I'm not sure that throwing money at it was really the right way, but was a pleasant thing to do.

Tony Wilson (00:29:56):
And what about living in America itself outside of work? How was that for you?

Tony Wilson (00:30:01):
I was lucky. The Bell, well, Bell Labs began life in Manhattan and then Bell Labs moved out to New Jersey and I worked at the Bell Labs place called Homedale that there were really two big ones. Murray Hill was the original one then Homedale was an offshoot and an offshoot of Homedale was a place called Crawford Hill, which is just a few well, probably about a mile away. And that's where the first satellite thing went from what I was lucky for the first time in my life to live on a beach, what, not, not actually on the beach, but within about 50 meters of the beach. And that afforded two things. One in the winter, it was extraordinarily cold and my car would freeze up. Even, it really was very cold, but from this beach, I remember lying in the water, having gone down and lying on my back and looking through my feet and through my feet, I could see the Verrazano Narrows Bridge and behind that the World Trade Center. And I thought this is not a bad view. Really This was pretty nice.

Peter O'Toole (00:31:27):
I just notice you're now lying down. You're a semi -beach bum at this point. Absolutely. On you understand biology. You like to, you probably prefer to lie down and just relax out here, Tony uh, are you a nightowl or are you an early bird or are you, I don't want either - just a midday person.

Tony Wilson (00:31:47):
No, I prefer the early mornings. I don't like late nights particularly. I mean, I do them from time to time, the idea of burning the midnight oil. I don't like, I much prefer to get up early.

Peter O'Toole (00:31:59):
So I also know you've got a passion for cryptic crosswords.

Tony Wilson (00:32:03):
I'm afraid, so, yep. Yep. I'm afraid.

Peter O'Toole (00:32:06):
So that, that arrives on your desktop at six o'clock, is it at the moment

Tony Wilson (00:32:12):
It arrives at midnight in the UK? That's to say I have a subscription. So to be perfectly honest, I do what is probably the easiest of the cryptics. I won't say which

Peter O'Toole (00:32:26):
No such thing as an easy cryptic crossword, I still just do not get them at all.

Tony Wilson (00:32:30):
There is such a thing as a really hard cryptic crossword, and so when I'm here in Texas, I'm six, eight. It depends the time of year, but right now we're six hours behind you. So 6:00 AM here is midnight in the UK. So I do tend to download the crossword in the evening and have a play about with it. And for reasons you will understand, you play around with the crossword and you can't do it. You then go and do something else, which in my case is going to bed. And then you wake up in the morning and suddenly number three down is easy.

Peter O'Toole (00:33:18):
Yeah. If it's come to come to you in the dream. Yeah, but otherwise.

Tony Wilson (00:33:20):
Yeah, absolutely.

Peter O'Toole (00:33:23):
I just keep me awake at night trying, to think about why I can't understand it.

Tony Wilson (00:33:27):
Well, sadly, that puts me to sleep.

Peter O'Toole (00:33:31):
So what else do you do to pass your time do you watch TV, what do you prefer TV or book?

Tony Wilson (00:33:37):
Book because of it's a trite thing book because the pictures are better. I mean, I've just the trouble with a book though, is you can't put the thing down. I mean, I just started reading. I, I have to confess to you. I'd never read Whisky Galore, the Compton McKenzie thing set in his fictional Hebridean Island until the last couple of days. And the problem is once you start to read this thing, I mean, it's a hilariously well-written thing. You get your teeth into, you don't

Tony Wilson (00:34:14):
Really want to put the thing down. So I am, I, I sort of you need coffee, which I'm afraid. I don't have it the minute I don't have you say, what do I love? What did I miss about being in the States? What do I miss about being in the States? And the answer is three things which have improved a bit. The three things that I miss when I lived in New Jersey was one bread, two cheese. The other one was espresso, which I see you are well stocked with. And I'm things have improved a lot, certainly down where ranches things improved tremendously when George Bush Jr. Was president his ranches in the neighboring county. And whether it was the visiting press pac or whatever, but the coffee locally improved tremendously. So that was good.

Peter O'Toole (00:35:17):
I've gotta say I, I, I do like my coffee. In a big way.

Tony Wilson (00:35:19):
Yeah. And I also like TV to be honest, but I tend to watch old things like old Sherlock Holmes things, old issues. This is a really embarrassing thing. Old episodes of Colombo, for example, I'm big Colombo fan, but.

Peter O'Toole (00:35:39):
That's a cryptic crossword thing, isn't it?

Tony Wilson (00:35:40):
Well, there probably is an answer to that.

Peter O'Toole (00:35:45):
I'm sure we can really work out with what's given to you along the way.

Tony Wilson (00:35:48):
Indeed. Indeed.

Peter O'Toole (00:35:50):
It's always a, a good summary the art of an abstract indeed. So actually, what are you driving? I know in the UK, you love your car. Yeah. I think I have, there you go. Yes, that's right. I believe that's a, maybe not your precise one, but.

Tony Wilson (00:36:14):
It's not actually my car. Cause I would try and because I wasn't expecting to be here in Texas, as long as I have am. I haven't got a picture of my car, but that's basically what the thing looks like. It's that color and that same model. And I've been lucky enough to have Jaguars since, well, my that's a picture of the in inside and amazingly, this picture I managed to find on the web is also got this sort of gin, gin, and tonic holder open, which would never happen in my own car of course. And so they just beautiful cars. There's no two ways about it. And

Peter O'Toole (00:36:57):
So what age is it? Which year?

Tony Wilson (00:36:58):
Oh this one? Oh, this one's quite old. I've had this one for a while. This one's 2000. I think I may be wrong on that.

Peter O'Toole (00:37:05):
It is a first series XJS.

Tony Wilson (00:37:05):
Ufirst you know, more about this than I do it too. To me, it's a nice blue car. Uunlike many of these things, the, I don't want to be rude about modern cars, but they're not often as elegant as the older ones.

Tony Wilson (00:37:26):
Some are. I completely agree. But I like the shape of this car. It's a beautiful thing to drive. Downside, you have, hasn't got sat nav. So I have my own sat nav, which is fine. And with the satnav you can learn any language you like, you just tune in and you end up learning the Latvian for bear left and so on, which I can't remember. And so they're interesting things.

Peter O'Toole (00:38:00):
So what was your first car?

Tony Wilson (00:38:02):
My first car was a car, which I inherited from my father. It was a Ford Cortina, and it was a very nice car, but it cost me a lot of money in the sense that I learned, one thing I learned from the traffic warden, I learned what operating a vehicle meant because the thing that the problem with the Ford Cortina at that time was that, Oh, there was a technique, I think it was called under sealing where you had your car under seal such that the car wouldn't rot from the underneath. Well, what happened with the Ford Cortina of that generation was as,uwater and yuck were splashed up,ufrom the front wheels in particular. It could cause the,ufront wheel, the bit at the top of the front wheel to,urust through. So this car was of a considerable age and the front wheels had rusted through. And the traffic warden determined that I was quote, 'operating a vehicle in an unfit state'. And I said, look, you've given me this ticket at three o'clock in the morning. I wasn't operating anything. I learned then that operating meant have the ability to operate should you so wish? So there shortly thereafter, I got rid of the Fort Cortina and replace it, of course, with a Jaguar.

Peter O'Toole (00:39:33):
You said it was costly, but it's a 3.2 or 4 liter.

Tony Wilson (00:39:38):
Oh, this is 3.2. The, the earlier one was 4 litre.

Peter O'Toole (00:39:44):
Yeah. And you know, the petrol prices back in the UK, that's supposed to be costing you more than it would cost to repair your Cortina.

Tony Wilson (00:39:51):
It is cheaper by far to go everywhere by Uber, obviously, but it's not so much fun. You do have to close your eyes a little bit when you fill up the the gas. But even I even do that here now. I mean, when I lived in New Jersey petrol in this country was just on $1, per gallon in Texas where taxes are lower. In fact, there's no state income tax, for example petrol gas was under a dollar per gallon. That's no longer true, but you're right. Quoting the price per liter makes people like me not understand how much, how expensive it is until you actually come to pay the bill. But yeah, you're right. Painful.

Peter O'Toole (00:40:44):
I love the fact in the UK. We buy it in liters and yet our car quotes in miles per gallon still.

Tony Wilson (00:40:49):
Yeah. That, well, there you are things we understand.

Peter O'Toole (00:40:54):
He sits on the fence with everything don't we? Yeah. Bringing it back. You then came back to UK, you had the confocal ideas and it became much more widely accepted. I think in the publication, was it? Amos and White?

Tony Wilson (00:41:08):
Yup. Yup. That's the one I think which got biologist interested in. That's what we want to be able to do. Yep.

Peter O'Toole (00:41:16):
So how to get it to market. You got that, I guess through the BioRad and the MRC series.

Tony Wilson (00:41:22):
Yeah. We went to market early. We went to market at the wrong time for anyone who's thinking of it. We went to, Well, we went to market just as I went to the States and we went to market because a lot of people I have to say, not biologists were mainly in the semiconductor area. We had another technique, which I won't bother to go into, which we called Obick, which allowed us to probe properties of semiconducting materials. Actually look at the way they behaved in a way which gave back information about minority carrier lifetime and so on, and also purity of the material, whether it but so that was all of interest to the semiconductor people. And we set up a company, Oxford Optoelectronics to basically sell this. And we sold a few. We sold the first one, which actually was confocal, although probably not very good at being confocal to Texas Instruments.

Tony Wilson (00:42:42):
And then we also built instruments for, for IBM and a bunch of other people, but not really in the bio area. Then the Amos and White paper came out and we of course thought, well, yeah, obviously you could do that. But of course we didn't know. Cause we weren't biologists that being able to obviously do that opened a whole load of biology where people had said, well, at least as I understand it, we believe this is what happens. And you could now see, yes, this actually is what happens. And you could see things a lot more in parallel to them coming out with that frame grabber cards were becoming available. One was able to scan quickly, maybe not quite real time, but still pretty fast in parallel with that image processing her come leaps and bounds image processing in the seventies just wasn't there.

Tony Wilson (00:43:42):
You could couldn't do it. And I think that's a parallel which goes on until now the video games market has made microscope imaging stuff beautiful in a way that if there been no video games market, no one would have put it in. So you can now do inexpensive things which would have cost. Well, which would it be prohibitive in the past? So I think it's this wonderful thing of parallel technologies improving the laser improved. We started off one of the first projects we had way back was harmonic generation microscopy, second harmonic, third harmonic. Because again, that was probing the actual properties of the device, but the only laser we had, which this chap Rudy Kompfner, was able to borrow a homemade version from Bell Labs. We had a Neodymium YAG laser. This is a infrared laser it's power was one watt? It was a CW Laser. Yeah,

Tony Wilson (00:44:51):
A laser that the health and safety people would not allow us to go anywhere near in the lab now. And we were able to get 2nd harmonic images. We were able to melt materials very easily, but we were able to get harmonic images. A few years ago in the lab because of the tremendous developments in laser technology. We were able to do third harmonic generation, which is a parametric process, or you're not dumping energy into the device. We were able to get third harmonic generation of living C. Elegans uh nematode, wiggly worms and it's living and you can see this. You can also see living embryos technology, which you couldn't dream of. Uh years ago, but they paralleled the development of other tech knowledge has made a big difference.

Peter O'Toole (00:45:58):
So you had these ideas, you took them to companies, different companies ran with elements of those ideas. So it's quite, you've got your . How do you balance your academic side and your commercial side? I know now that there's Aurox, which is really pushing forward in developing lots of new products that take a lot of time and energy along with the academics. That's how, I mean,

Tony Wilson (00:46:23):
When we first set up Oxford Optoelectronics Limited. And after a while of trying to do everything ourselves, and we then got into bed with the, a company called Dubilious Scientific, which became Laser Sharp, which became BioRad which became BioRad. Yeah. I mean, I've got those in slightly the wrong order. When we were doing all of that university spin-outs do use the present words were not popular and indeed, I'm not sure they were strictly approved all of them that we, we didn't keep it secret that we were doing that, but we didn't make a big deal out of it when we came to set up or Aurox by that time spin-outs were more useful and we set Aurox actually. Oh, I was about to say earlier on, I said, you know, when we set up Oxford Optoelectronics, maybe it was a mistake.

Tony Wilson (00:47:33):
And what I mean by that is we set up a company to sell a confocal microscope when no one had heard of a confocal microscope. So much of the time we spent doing what one of my colleagues calls missionary work. And so you're spending all your time telling people what a confocal microscope is, why it might be a good idea. And of course you have a product that doesn't quite fill those requirements because we were still at that point stage scanning then other people came along the Brad Amos and John White thing was a very good example of how you could turn these ideas into a biologically friendly form. And that was clearly the way to go BioRad, saw that, and that's the way they went forward. And that was, was obvious, but we had, I'm not taking credit for this, but if you're doing the, the missionary work, you're doing everybody a favor apart from yourself necessarily.

Peter O'Toole (00:48:41):
They're not your academic side anyway, cause that, yeah, I guess you spin out is academic side.

Tony Wilson (00:48:47):
And the academic side, as I was saying at that point, tehnology, you start off by saying, well, why did you do confocal the way that you did? And the answer is because you had to, you had to have the point source, you had to have the scanner. You couldn't do it any other way. You know, an ordinary light bulb isn't sufficiently bright. You can't scan it around, but of course, as all this was going on, technology was improving. Lasers were improving. They were becoming semiconductor. They were available over a wide variety of wavelengths. Also the CCD camera had improved leaps and bounds, partly because I got, I mean, one of the wonderful things about being an academic is you get invited to conferences all over the place and 20 years ago, or so the scientific CCD for astronomy or for spectroscopy was becoming very important.

Tony Wilson (00:49:53):
And I was luckily lucky enough to be invited to a number of conferences in essence, aimed at imaging where the light levels are very low. So it was a meeting of people who were doing imaging combined with people who were trying to detect incredibly weak signals. And this was run by a spectroscopist actually a spectroscopist from East Texas, and he ran these meetings in the Cayman Islands in December. So that was about as much of an impact as much of a come on to get interested in low imaging in low light levels. That introduced me to the CCD camera in anger and also introduced me, told me pretty clearly that the days of wet of wet photography were over of the companies who were there. The one that sticks in mind was Kodak. And I thought if Kodak are getting interested in this, this is going to be the way forward.

Tony Wilson (00:50:58):
So the CCD camera came along, which could detect weaker signals. So you say to yourself, well, what is it you want your microscope to do? And the answer is you want it to do everything the regular microscope could do without any doubt. You don't want to throw any of that's away, but you want it to have this axial resolution. So the question is, let's start from scratch. Let's say, okay, we've got the conventional microscope. We can get the image electronically. Now, trivially easily. You just stick a CCD camera. There there's no need to scan, but you still have to get the thing to give you the three dimensional imaging. How on earth can you do that?

Peter O'Toole (00:51:46):
Which is where you've been heading on.

Tony Wilson (00:51:48):
Really? We were heading recently. So plan a was to use structured illumination because you like to do the mathematics. It turns out that if you do build a con focal again, I won't go into fine detail. You illuminate the specimen with light from a point source, mathematically, a point source. If you think of it, in terms of spatial, frequencies contains all spatial frequencies. So you illuminate the specimen with all possible spatial frequencies. If you have a point detector, you detect it with all possible spatial frequencies. If you have a conventional microscope? You have a plainar detector. That's got one spatial frequency. So with a conventional microscope, you detect one spatial frequency with the conventional. You detect all of them. And with the convention on not only do you detect all of them, you actually detect an average over all of them. If it's an average, it can't be the best. So the thought therefore is let's not, that's not the illuminate with all spatial frequencies. That means all angles. What let's illuminate with one, and let's pick that one. Do the mathematics, such that it enhances the confocal effect.

Tony Wilson (00:53:14):
It gives you the optical sectioning. So the idea was let's illuminate with a single spatial frequency. That means a single sinusoidal pattern. Yeah. And let's look at the image that we get and what you get because you have to image you can't image with a single sinusoidal pattern cause you can't have negative light. So you have to have a background with this pattern superimposed. So what you get when you look with your eye is you get a conventional image due to the background, superimposed upon which is the confocal image, but modulating with this fringe pattern. So then you say to yourself, okay, I can in the computer, I can get rid of the background. That's relatively easy. And so what I then get is the image I want, but it's modulated plus minus by this fringe pattern. How do I get rid of that?

Tony Wilson (00:54:15):
Well, you get rid of that by taking more than one image and you play abracadabra in the computer and you get out an image. So that's right. So we then thought, okay, we will license the patent on this. So we licensed the patent and there's a story behind that, which I won't bore you with to a company in New York State. And they came up with a product called the Opti-grid. And that worked quite well in parallel with this Zeiss came out with a product, they call the Apatome, which is exactly the same thing. We took the view, Zeiss were being a bit naughty in what they were up to, which is a view, many people shared. However, we took the practical view that we're getting all this free publicity for the technology from Zeiss. So why argue now my prejudice comes to the fore, which is to say that you only use a computer when you have no choice.

Tony Wilson (00:55:20):
It's the, it's, it's the port of last resort. You don't use a computer if you can do things more elegantly optically. So in so, the idea is how can you get rid of the fringes from this composite image optically and for the electrical engineers, you do the spatially equivalent of locking the modulation. So you have a fringe pattern that you illuminate, and you have a fringe pattern in the detection plane. And in order to do the demodulation, you spin these things, you rotate them and you time average, which in English means look with your eye, at what you see. And if you do that again not going into too much detail, you can extract both the conventional image and the confocal image. Cause it's important to get the conventional image as well because to paraphrase, I can't remember who, but I quite like it. What's the advantage of a confocal microscope.

Tony Wilson (00:56:30):
You only see the portion of the fixed specimen that's in focus. What's the disadvantage of a confocal microscope. You only see the thin bit that's in focus. So you want to see the whole specimen to find the bit you're interested in. Then you want to switch to confocal. This approach allows you to do both at the same time. In one part of the screen, you can have a conventional, the other part of the screen. You can have the confocal. The fact that everything is spinning and CCDs have improved tremendously real time imaging is easy. Even higher speed imaging is easy. If you have enough photons, it's easy. And by this technique, you can do confocal like imaging, basically with a regular microscope, you could take the microscope. And maybe if we speak nicely to The Museum of the History of Science, we can take a hook type microscope and turn it into a confocal.

Tony Wilson (00:57:31):
We have the technology. So to do at that point, we thought let's not sub-license this because we also thought actually pompously arrogantly. If you like, we can do better. So we decided to do it better by ourselves. This product became the Vivatome from Zeiss. We supplied it to Zeiss at that point, it became, I can't remember what from Andor we supply to Andor it's now in a more in a improved state. If I can do the quick add it's the Clarity from Aurox, or also available as the sort of coffee machine, the espresso machine instrument as the my own product it's called as the Unity . And also comes with our own fabulous software imaginatively called Visionary, the whole thing, being driven, by a tablet. Anyway, that's enough of that.

Peter O'Toole (00:58:46):
Interestingly way back at the time of the Aurox coming through and before Zeiss taking it as a vivatome, actually, I was offered to beta test it for one of the other companies who was investigating it at the time. So you may not have even been aware of who they passed it to, to beta test. Perkin Elmer were interested at that time. Yep. Nope.

Tony Wilson (00:59:08):
I, I was aware, I was aware of that because although there are secrets, they are that they're not quite like Oxford for secrets. I mean the, okay, what's the theme. What does the word strictly confidential mean?

Peter O'Toole (00:59:27):
I don't know. No one's ever told me

Tony Wilson (00:59:29):
Strictly confidential means you only tell one person at a time. Very good. Very well done. So yes, there are confidentiality, but yeah,

Peter O'Toole (00:59:39):
A couple of quick questions just to end on. Okay. Yeah, actually, I'll go to you're British. Where, where were you born?

Tony Wilson (00:59:51):
I was born in a place called Sutton in Asheville, which is near Mansfield, which is in the Midlands in Nottingham. It's on the Nottinghamshire Derbyshire border too.

Peter O'Toole (01:00:04):
Hi, come, you are Yorkshire cricket fan then ?

Tony Wilson (01:00:06):
Ah because at the age of two, my parents moved to Rotherham. And cricket was my father's great sport. And my mother liked cricket. Also. She was born and lived in Derbyshire and she would often take the bus to Nottingham and there will be a professional cricketer who would often take the bus with her. And at those times there was the amateurism, the professionals, and this professional cricketer, you got to know a bit would go on the bus to Nottingham. And as it turned out to play for Nottinghamshire, and he will be wearing his cricket whites on the bus in order to go out and play. And he was a chap called Harold Larwood.

Peter O'Toole (01:01:01):
Okay. Just, just, this unknown cricketer.

Tony Wilson (01:01:06):
Indeed I, and then cricket was, was, was, was what I played at school. And family holidays always ended up in Scarborough for the Scarborough Cricket Festival at the end of the summer, which was fantastic.

Peter O'Toole (01:01:20):
I notice, you've actually kept your cowboy hat on for the entire interview chat. So I kept my Yorkshire hat just for you Tony, well, yeah,

Tony Wilson (01:01:31):
You mispronounced it. It's inasperate, the H

Peter O'Toole (01:01:37):
I'm not a true Yorkshireman Tony. I'm a Brummy.

Tony Wilson (01:01:42):
Neither am I I'm afraid it's like.

Peter O'Toole (01:01:46):
Two final questions. Yeah, of all the publications that you've done and authored.

Tony Wilson (01:01:51):
Oh, wow.

Peter O'Toole (01:01:52):
What would be your favourite one?

Tony Wilson (01:01:54):
Oh, goodness gracious. They're all things that I'm proud of. Otherwise I wouldn't have published them. Some of course, one is more proud of than the others. I think one that I quite like, and it's, it's not one the world will particularly have seen, it was written. It was, it was looking at the role of polarization in microscope imaging. Now people often use polarization to do high angle vectorial theory of this, that, and the other, and to first order. And I don't wish too. I mean, I've done it as well. It doesn't tell you a great deal that if the microscope behave dramatically different than you would predict from scaler theory, you'd need to be a little bit careful. Now, of course, if it's a polarization effect you're looking at, then that's completely different. But I was always interested to wonder whether some of the things we saw in a polarization microscope were actually polarization effects in the sense of the specimen being birefringent or not, or what physicist call form birefrigers i.e. Scattering and the form of the material gives rise to a change in polarization.

Tony Wilson (01:03:28):
And in one things that we always look at is a point scatterer, because you can look at resolution on this, that, and the other. And there was one paper we did looking at, Oh, we had also, of course, by that time, realized that the confocal was the instrument of choice. If you were doing polarization imaging, because one of the things you want in a polarization sensitive microscope is as high an extinction ratio, as you can get. And for fundamental reasons in the conventional microscope, that extinction ratio cannot be zero. I won't bore you with why in the confocal broadly because, you're averaging over intensity in the confocal where again hand waving and you're averaging over amplitude, you kind of get an infinite extinction ratio. So we were playing around with this and imaging point. Scatterers looking at the polarization property between cross polars, with cross circulars, this, that, and the other, and you get the most beautiful shapes of the image spirals.

Tony Wilson (01:04:36):
And goodness knows what, when you slightly de-focused, which you can't explain in any other way, and you see them when you're imaging biological tissue, you look at some of the images that for example, Rudolph Oldenburg and Shinya Inoue were obtaining, and you can explain these things beautifully. Does the world care? Probably not, but it's beautiful. You can have the image. And the theory is very, very simple. You do have to do the vectorial theory, but there's a point to doing the vectorial theory. It's just very, very pretty.

Peter O'Toole (01:05:10):
I think I actually polarization in lights. I think there's a long way to go with that in. Absolutely. So the next 10, even 20 years, I think really starting to move into that area to gain information that we just can't see or capture at the moment.

Tony Wilson (01:05:27):
And there's one other paper I wrote, which was also on polarization where we actually built an electro optic device, which rotated the polarization and had a locking things. And you can basically map out the polarization states, the kind of thing Rudolph Oldenburg, was up to, and you can do it in more or less real time. That was also a very pretty a paper. I have to plug that one that was published in the Journal of Microscopy. The other one I'm afraid was not.

Peter O'Toole (01:06:01):
Heavy, old journal as well. And still one of the best for microscopy itself. I have to stop at this point. I think we could go for another hour quite comfortably. You have been brilliant.

Tony Wilson (01:06:14):
Thank you, Peter.

Peter O'Toole (01:06:16):
And you wrecked my hair by the way, putting that cap on. I shouldn't do that.

Tony Wilson (01:06:19):
I take my hat off cause I actually had my hair cut yesterday in a lockdown. And I have to tell you it's the first time I've had my hair cut, wearing a face mask. The main reason for wearing the hat.

Peter O'Toole (01:06:34):
At least you could get it cut. My son is still cutting my hair so.

Tony Wilson (01:06:39):
I could comment on that.

Peter O'Toole (01:06:40):
He's very good at it. I've gotta say Tony. Thank you very much. See more of your developments in the future.

Tony Wilson (01:06:49):
Okay. Thank you.

Intro/Outro (01:06:54):
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.