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Hari Shroff (NIH)

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About this episode

#7  Young, successful and still so disarming. In this episode, Hari Shroff (NIH) reveals what it was like to work in the exciting area of Super-Resolution microscopy during its infancy, and discusses working in the early days of the Howard Hughes Medical Institute’s Janelia Farm Research Campus.

Hari discusses his latest work and the efforts that go behind such a high impact publication while also talking about the advice and patience he needed when setting up his own lab. Unwittingly, Hari and Peter O’Toole’s paths came very close as Hari spent some of his youth in Peter’s city of Birmingham in the UK, which unfortunately was not the place that it is thankfully now.

Thank you, Hari, for taking the time to chat, especially as he is juggling work with a young family, as well as his work family, which is evident from the interview.

Follow Peter O’Toole and the NIBIB on Twitter!

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Please note: this is a machine generated transcript that may not be 100% accurate.

Intro/Outro (00:03):
Welcome to The Microscopists, a Bitesize Bio podcast, sponsored by Zeiss Microscopy. The Microscopists series invites you into revealing, entertaining and personal meetings with the great microscopists of our time. Now over to your host, Peter O’Toole.

Peter O’Toole (00:25):
Hi, I’m Peter O’Toole and today with me is Hari Shroff from Bethesda, the NIH over there. Hari, hiya?

Hari Shroff (00:32):
Hi, great to see you. Thanks for letting me do this.

Peter O’Toole (00:35):
Pleasure and all the more exciting, cause I hadn’t realized when we set this up that actually, well, I guess we wouldn’t have realized that you just, just released a publication Nature Biotechnology.

Hari Shroff (00:46):
Yeah. Yeah. We’re very happy about that. That was a long time coming. So it’s nice to see that come out this month. Yeah.

Peter O’Toole (00:55):
So that was on a, actually the title is quite wordy. So, it’s actually multifaceted, there’s a couple of different new developments within that one publication isn’t there? And I looking at the CPU, the algorithm software, and also the dual view approach.

Hari Shroff (01:12):
Yeah. There’s a lot of stuff kind of packed into that article. So it’s, it’s, it’s fairly dense. And you know, I guess the overarching theme is trying to make some of the processing that we do faster because that certainly bottlenecks our lab. And, you know, we figured it probably bottlenecks many other labs as well. You know, sort of after you get the microscope image you need to post-process it. How do you do that quickly or how can you do it more quickly? And so that’s what that article is kind of broadly about.

Peter O’Toole (01:42):
How many years effort do you think was behind that publication?

Hari Shroff (01:47):
You know, we, we first started sort of getting down into that maybe five years ago and then, you know, sort of picked up steam after that. But the first inklings were probably in 2015 and then, you know, there’s the whole sort of year long saga of getting it published. Right. Which also takes time sort of sending it out, getting the reviews back which is, which is kind of lengthy. So yeah, years of, of time.

Peter O’Toole (02:15):
And how many staff? Yes. How many PhDs, postdocs?

Hari Shroff (02:21):
Uh you know, I innumerable staff years because there were the sort of core group of people in my lab. And then we worked fairly closely with other other researchers in China and at University of Chicago. And then there were all of the biologists that we enlisted to help with sample prep. So, so many, many staff years, it was really a collaborative effort which we’re just sort of lucky that you know, that that’s becoming in some ways easier and easier I think to do.

Peter O’Toole (02:49):
So, so that it was interesting. It’s amazing the number of years that it can take to get a publication out. And the cost of that, the cost of science is huge because of all that effort, and the team efforts that are needed behind it. It was interesting you said you recruited loads of biologists, cause I guess, would you count yourself or class yourself as a biologist?

Hari Shroff (03:07):
I’m kind of uncomfortable with, with labels, but I think most people would say that I’m not a biologist. I love biology and being able to contribute to biology with some of the tools that we built and we have a couple of biological projects in our lab, but I, I guess I even, I wouldn’t characterize myself as a biologist, so we benefit greatly from, from collaborating with, with bonafide biologists.

Peter O’Toole (03:32):
So you started out if I remember correctly, your undergraduate is bioengineering?

Hari Shroff (03:36):
Yeah, exactly.

Peter O’Toole (03:39):
And then was that straight then with Eric Betzig or was there something between that?

Hari Shroff (03:45):
So yeah, between the bioengineering undergrad and the time with Betzig, I did a PhD at UC Berkeley doing biophysics. So the kind of common thread, I guess you could say both from the bioengineering and the biophysics was kind of an interest in tool building you know, very different kinds. But the sort of love of instrumentation really kind of took off as an undergraduate. And then I did more of that as a PhD student at Berkeley and then with Eric Betzig in microscopy.

Peter O’Toole (04:15):
So your love for instrumentation, was that always microscopes?

Hari Shroff (04:21):
So you know, it’s, there’s always a link to imaging, I would say. So as an undergraduate, I I played around with honeybees. So the guy that I worked for as an undergraduate, was actually in the chemistry department, he was an analytical chemist that had invented a pressure sensitive paint that he had used to coat airfoils. So like, if you want to understand the pressure distribution on an airplane wing, he had actually marketed this paint to Boeing and, you know, by the time I joined his lab, he was kind of getting close to retirement, but he had this crazy idea of using this paint to try and coat the surface of a honeybee wing. So the paint gave off a signal, a phosphorescent signal that was inversely proportional to the amount of oxygen. So it was an oxygen sensor. And the idea is that when a honeybee flaps its wings, his dream was to try and see if you can actually measure that distribution of oxygen pressure using this paint.

Hari Shroff (05:18):
And so it was my job to kind of figure out how to put the paint on the wing of a honeybee and then image it. So not exactly microscopy, or sort of microscopy, but we weren’t using microscopes to try and do this.

Peter O’Toole (05:32):
Did that work?

Hari Shroff (05:32):
No. So it didn’t, it didn’t work like we hoped on the honeybee because a honeybee is just too fast. So it beats its wings on the order of hundreds of frames per second. And, you know, we were we just didn’t have the signal to noise ratio we needed, but in the course of trying to do that, I learned a ton and it really got me interested in research. And I actually built a very crude instrument. What we called the pressure sensitive microphone. It was just a tube of PVC pipe with a fin, a film of this honeybee of this polymer containing the the paint that we put on the honeybee at one end of the pipe and then a speaker at the other end. And so we would fire sound waves at one end of the pipe and then detect the response using the paint. So it wasn’t like a microscope in any conventional way you think about it. You weren’t looking at anything, but it, but it sort of served the same purpose in being able to characterize the response of this thin film of phosphorescent paint in response to the sound waves.

Peter O’Toole (06:36):
It’s quite neat. So I guess even then not fluorescence per se, but still the illumination of light from, from chemicals, from there onwards as well. So it’s kind of brought that both those parts together quite nicely. So when was the first time you actually used a microscope properly?

Hari Shroff (06:53):
So I don’t know about properly, but the first time I ever used a microscope, I was probably a kid and my parents brought, bought me one of these cheap microscopes that I just, you know, it had a bunch of kind of prebuilt slides that I put on the microscope. And then I think there may have been some ability to kind of make my own slide, but it was, it was, it was very very basic, you know, so like I, I might’ve collected some leaves or something and tried to magnify those. And that was definitely fun. But the first time that I actually use a microscope properly would have been, you know, much later probably, you know, as an undergraduate or possibly even as a graduate student when I was trying to make my own microscopes. So, you know, there was, there was a bit of a gap in there before I used a proper microscope.

Peter O’Toole (07:39):
So, so actually a question. So you, you actually spent a long time in the UK if I’m correct?

Hari Shroff (07:47):
I did. Yeah, so I was, I was born in India, but then when I was one year old, my parents moved to the UK trying to get better jobs. And so they were both medical doctors and they kind of trained in the UK. And we moved around a fair bit in the UK, but, but from one to nine actually grew up in the UK in different towns in England.

Peter O’Toole (08:08):
So where abouts?

Hari Shroff (08:08):
So a lot of time in Birmingham and then some time in Stoke-on-Trent which I kind of kind of remember, remember fondly and then and then moving, moving over to the US.

Peter O’Toole (08:22):
Yeah. So I’m a Brummie as well. So for those who don’t know what a Brummie is, Brummie is someone who is from Birmingham as a city second biggest city in the UK. So actually I am a Brummie I guess but born North, went South. It was an interesting place years ago. I go back now, it’s, it’s a really multicultural and diverse, vibrant city it’s really reinvented itself, but I’m not so sure it was like that when I was a child. Certainly I remember going in as a teenager into the city and it was, there was some places that were good. There was other places that you were not so good. I don’t know what your memories are like of the city at the time.

Hari Shroff (09:01):
Yeah. Yeah. Akin to yours in some ways, so I I’ve kind of mixed emotions about Birmingham. I mean you know, like, like you said, I’m sure it’s much better now, but when I was there as a kid, I, you know, some of my memories, unfortunately, were of other kids, other kids calling me Paki as, as a school child. So that was kind of a rough, rough time growing up there you know, one of the good things about sort of England in general and the educational system there is that I felt that I was way ahead of my peers when I came to the US. So the kind of educational system was, was great, but but it was kind of a rough time growing up as a kid in parts of England for this reason.

Peter O’Toole (09:40):
Yeah. I can imagine areas that it would be like, but certainly it’s, I, it, there’s always going to be areas, I guess, that are still not great, but actually Birmingham as a whole is actually, yeah, it’s a really cool place to go now. So I still live near there. So I visit there, but it’s, it’s quite an attraction though. People actually visit Birmingham, they would go to Birmingham because they had to, whereas now they would actually choose to visit it.

Hari Shroff (10:06):
That’s, that’s awesome. So the kind of industrial feel is turned around. Yeah.

Peter O’Toole (10:09):
Very much so. So so what do you miss?

Hari Shroff (10:16):
You know, yeah, I mean, I miss, I miss going for walks in the countryside with my parents. I mean, that’s something that we, we still do in the United States, but I just missed, missed the kind of lovely English hedgerows and hedge mazes. And I miss you know, parts of London. So I had, I have an aunt in London and we would sort of go there for a treat to visit her. I miss Trafalgar Square and Regents Park and walking around that area as a, as a kid. You know, and I, I, I frankly miss my nannies. So, you know, the, the notion of like an English nanny is something that was, you know, my parents both worked a lot when I was a kid. And so I had great great nannies who taught me all sorts of things, you know, as, as a, as a child that I miss all of that too. I have very fond memories of growing up in England.

Peter O’Toole (11:01):
Oh, that’s good. And come on, you were in Birmingham for nine years or roughly nine years. You must miss the chocolate.

Hari Shroff (11:10):
You know, I, I miss, I miss in general English chocolate and European chocolate compared to some of the crap that you get over here in the States. So I do, I do miss that too.

Peter O’Toole (11:20):
Yeah. I just, for you see look?

Hari Shroff (11:24):
Oh nice. Cadbury’s.

Peter O’Toole (11:25):
We’re kids, of course, of Birmingham confectionary,

Hari Shroff (11:27):
You know, it’s funny you say that I actually remember walking by a Cadbury’s factory and it probably was in Birmingham. I, I have vague memories of it, yes.

Peter O’Toole (11:37):
Yeah. So Bournville is, I’d say that was probably four miles up the road from where we moved when I was about six to the South of Birmingham. And it’s about four miles away from Bournville.

Hari Shroff (11:48):
Yeah. And it’s not that easy as you, as, as you say, to get that here, to get that sort of chocolate here in the States.

Peter O’Toole (11:54):
Good milk chocolate. I love dark chocolate but there’s always a place for, for Cadbury’s, for sure. We started talking about earlier. So you went to America, you went through your PhD days and then ended up at Janelia Research Campus. Or Janelia Farm as it was then. What was that like? Because that’s quite a different environment.

Hari Shroff (12:15):
It is. Yeah. I mean I would say that for a postdoc, it was an amazing environment in the sense that you could really focus on your research. I mean, there were very few distractions and funding was easy to come by at the HMI Janelia Farm. So these were some of the good things I think you know, one of the challenging things is that, that, that very sort of myopic view on microscopy and neuroscience meant that in some ways it was difficult to get a broader, broader view as to what was going on. And that’s one of the things that I liked very much about the NIH and I, and that I miss frankly, in a university setting, you know, so the, at Janelia, the dominant kind of life form, let’s say is the postdoc and the PI, and that’s great.

Hari Shroff (12:57):
But I do miss in some ways being around university campuses and the kind of broader exposure you get, but there’s no question that, you know, from my career being at Janelia for two and a half years was amazing. And know some of that was Janelia. Some of that was PALM and Betzig and sort of being at the right place at the right time. So it was, was in some ways, very lucky that I got into that. And it was, it was just luck. You know, I was finishing my PhD at Berkeley and wondering what to do for a postdoc. And I love microscopy, you know, I saw many of my peers at Berkeley going to all of these kind of wonderful labs, but in some ways standard labs, right. So there’s sort of this notion that, you know, as a postdoc, you have to get into a good lab and do a good postdoc to get a good position.

Hari Shroff (13:41):
But frankly, I had no idea what I wanted to do when I was finishing my PhD. And when I was wondering about that Betzig rolled through Berkeley, kind of an unknown, you know, he had spent a decade plus basically in his living room, dreaming up microscopy ideas. And he was just, he, he himself had just gotten this job at Janelia Farm. And so he gave this talk on what would eventually become the precursor of the Lattice Light Sheet Microscope, lattice microscopy. And his talk kind of blew me away. You know, he was a tool builder. He’d been out of the business for a decade, but he really wanted to build microscopes that could enable biology and something about that spoke to me. So I remember speaking to my peers, sort of telling me, what the heck are you doing? You know, this guy has been out of science for more than a decade.

Hari Shroff (14:28):
What is Janelia Farm, and why would you go there? So this was a big risk at the time. He was in some ways kind of a no name getting back into microscopy and Janelia was also unproven at the time. You know, I was one of the first a hundred people to go to Janelia, but you know, something about his talk really spoke to me. And I, I liked the idea of working in kind of biological Bell labs environment and this, this was for better or worse, it was the right move, you know because I worked very closely with him and I, again, just luck, I happened to get into the PALM STORM business early. And I’m not doing that anymore. You know, like when I started my own lab at NIH, I could kind of see the writing on the wall. I didn’t want to keep doing that. But, but there’s no question that, that this was luck favoring the prepared mind and being able to take a risk, you know, paid off in this, in this video. So we can talk more about that if you want, but I think it was the right move for me at the time.

Peter O’Toole (15:30):
I love the way you said you could see the writing on the wall for PALM and STORM. In what context? It’s all yesterday’s work.

Hari Shroff (15:40):
Yeah. So, so, you know, for two and a half years with Betzig, I kind of lived and breathed PALM. I mean, that’s all I did. And, you know, there was a ton of developmental work that had to be done on this technology. I was late to the party, to the party, you know, Betzig again, Xiaowei Zhuang and Sam Hess’s papers had all come out before I joined Betzig’s lab, but there was, it was clear, there was a lot of work that had to be done, developmental work. And I was fortunate to do all of that. At the same time, after doing my postdoc, I had done so much of that stuff that I was sick of it. And one of the things that drew me to the NIH is that my the person that recruited me there and eventually gave me a job, Richard Leapman, you know, he said, when I joined, he said, I don’t want you to be doing the same thing in five years.

Hari Shroff (16:20):
And that was aligned perfectly with where I saw myself, because I didn’t want to be doing STORM development in five years. When I say I could see the writing on the wall. I meant that I could see as I was doing my postdoc and many other people kind of getting in to this field. And as a technology developer, I just didn’t want to sort of be part of that bandwagon, you know, which isn’t to say that there wasn’t and hasn’t been fantastic development work in that area. I mean, after all it won a Nobel prize, but I just thought it would be easier if I could start to kind of do other things, you know, in my, in my career. And so that’s what I meant, no diss on the wonderful development work that has been done by many other people in that area.

Peter O’Toole (17:01):
Too late, you’ve done it. You’ve dissed it.

Hari Shroff (17:03):
Yeah, yeah. Maybe I have, yeah. A little bit. So, so that’s sort of what I meant. And I just wanted to kind of move on to other things a little bit.

Peter O’Toole (17:12):
I think you’re right there, because as you say, once it’s developed, the big bangs happened, it becomes a very crowded market with relations and techniques to fill different niches, which are very needed, but maybe not so big an impact on the broader field, whereas you’ve gone off, developed your own and really moved into an airway where made your own name certainly through the Lattice Light Sheet and the algorithms being applied for that speeding it up. So how did you find setting up your own lab?

Hari Shroff (17:42):
Intimidating and, and, and difficult? Yeah, so I I got some good advice when I was getting into starting my own lab, which is that you want to start small and that the people you really hire in the beginning can make or break your lab. And so I really took that to heart. And in fact, you know, when I started, I, by the way I wasn’t involved in any of the lattice light sheet work that all came after me, but I, I w I, I was interested in light sheet microscopy. And so, you know, I, I had just a few ideas, you know, I wanted to kind of extend PALM some of the work that I did in Janelia. In fact, all of it was all limited to 2-D and I wanted to try and do three dimensional imaging and sort of, as you say, kind of make us make a name in that area.

Hari Shroff (18:26):
And so there were a few ideas that I had when I started my own LAB, I wanted to do 3-D PALM. So that’s one of the first projects that I did with my postdoc. And, but then I wanted to move on to other stuff, you know, in, in 3-D imaging. And so I knew that I wanted to do something in light sheet microscopy that I, you know, I, I, I was kind of interested in structured elimination microscopy as well, but I had only a handful of projects when I started. And I re I really only had, had a handful of people. I think I hired one post back sort of similar to somebody who had an undergraduate degree and worked as a technician. And then I took my time hiring postdocs, but the first few years I had just two and they were both excellent.

Hari Shroff (19:07):
So so to answer your question, I mean, it was intimidating and difficult, and the way I kind of dealt with that is I tried to work on just very few ideas and invest a lot of my own energy in making those work at the beginning, so that I kind of had a foothold when I started my own lab. And I feel like that really was the right strategy for me because having a bit of success builds confidence, and it kind of gave me the confidence to know that I could do this by myself and with the help of my lab. So that, that’s sort of honestly how I felt in the beginning, you know, I, and there’s one story that I remember that when I, so when I just came in my lab space, wasn’t ready. And in fact the NIH is great, but one, one, I wouldn’t say failing, but one issue is maybe this is characteristic of people everywhere, when they start their labs.

Hari Shroff (19:53):
But for nine months I was in a conference room, where I would order equipment and it would land in the conference room and a surprising amount of science got done. So we had an optical table and, you know, we, I don’t know if we could even float the table, but we started to build stuff on that table and at least hammer out some of the microscopes. But but the kind of one moment that I remember, so I, you know, I came in on my first day into this conference room and I think I just had a laptop that had been ordered for me and some Thorlabs boxes. And I had a desk that I had pillaged from some other surplus, and I sat down and I, I sat down with my laptop and my, my deputy director walked in with a laptop. And he said, he gave me the laptop and told me how to connect to the internet.

Hari Shroff (20:36):
And he said, well, I’m sure you must be very busy now. And he left me to it. And I started to wonder, is this the right thing? Like, what am I doing? You know, like sitting in a room, essentially, an empty room with this laptop and some Thorlabs boxes. And I was wondering what the heck I was doing. So that’s how I started my lab. I started without clean water and without any microscopes at all, all of which I built. But I was fortunate to be in a very supportive environment. And I made a point of emailing different PIs in the Institute and having lunch with a different person every day for the first few months to kind of, you know, start to know what was going on at NIH. And so that’s, I just kind of tackled the uncertainty head on, you know, but, but yeah, there’s this fear, you know, as a new PI and in some sense aspects of that fear never really go away. So to all new PIs, I would just say, embrace the uncertainty as best as you can and know that you’re not alone and it gets easier if you can stick with it, because in the beginning you’re doing everything by herself.

Peter O’Toole (21:38):
So you’re in the lab obviously as well, quite a lot at the start as well. So has that changed, are you still in the lab as much as you were, or are you now more office bound?

Hari Shroff (21:48):
Yeah, so I am, I am more office bound, but I do stay very close to the research. And in fact, when my lab did get built, one thing that I insisted upon was that my office is kind of in the center of my lab. So if you were to come visit, which I hope you do at some point, the next time you can, you’d see that, you know, my lab is kind of arranged with optics labs around the office and my postdoc office is kind of right next to mine. So I I am much less like at the optical bench because as my lab has grown, I spend a lot more time managing my people. But I make a point of trying to speak to everybody in my lab, at least once a day, at least just to find out how things are going.

Hari Shroff (22:25):
And I really want to know how things are going in particular, how things are failing. I’m really interested in knowing that as a PI. And I like to stay very close to the research, but it has changed. So in the beginning I was kind of building the hardware until my postdocs told me that I shouldn’t do that, but they were better at it than I was, which is true. And now I spend more of my time writing papers and talking to people about their projects and strategizing about optical design. Every once in a while, I’ll write some part of a piece of software, but, but it, it changes – where it has changed for me.

Peter O’Toole (23:00):
So you’re asking your team about how they are or how the labs go. You also say, I certainly find, finding out what’s going on in their personal lives or being engaged at that as well is really important. It’s important for me, certainly to, to know what’s going on and for them to have an outlet as well. Cause they don’t always have easy outlets because a lot of them are transient. They come in from different places. They haven’t necessarily got a social circle. So yeah, I guess at the start, I bet you would possibly even go to the bar or eating out with them because you’d have landed their, they are you’re team, but that must have changed as well. And you have a family now.

Hari Shroff (23:38):
Yeah, yeah, yeah. It has changed. So, you know, one thing that hasn’t changed is, you know, like, like you said, going out for a meal, I try and make myself available, available for lunch every day with my lab, because I do think that’s one time, you know, they don’t always want to eat lunch with me, but at least that’s, I have to eat lunch too right, in the lab. And so that’s one time when I’m accessible, but you’re right. It’s changed. And you know, more recently it’s changed, like you said, because I have a family, I have a daughter who’s a year and a half old and that, that has kind of sucked. There we go. Yeah, there she is.

Peter O’Toole (24:07):
She’s very cute.

Hari Shroff (24:08):
Yeah. That’s, that’s Amelie a few, a few months ago now. So maybe a year and a few months there in that picture and yeah, that, you know, she, for better, or for worse has kind of sucked all the energy out of my life after the, after the science, it’s kind of an all a full time job outside of science.

Hari Shroff (24:26):
Right. It’s being a dad is as I’m sure all of the dads know who are listening to this. And so there is, there is less time for doing things with the lab, for example, afterwards, you know, I I like to climb em every once in a while I can go climbing with people in the lab or even we have a climbing group. There we go. Yeah. Thank you. Outside the lab, other postdocs and other PIs at the NIH. So that’s one outlet for me outside of the lab and outside of my family. But, but all of that has been made more difficult right now anyway, by, by my daughter, because I, I like to as much as possible share the duty with my wife, even though it’s impossible to share, you know, I can never replace the mom part of my, my wife. Right. But, but I try when I’m home and in the morning, somewhat.

Peter O’Toole (25:11):
So you say, you say that, but is this not your daughter on a climbing wall, so you’re not trying to combine everything here?

Hari Shroff (25:17):
Yeah. I, I would love to get her on a climbing wall as soon as, as soon as she’s able, and now she’s kind of running around, but I like to this, is in a playground near our house nearby where there’s a mini kind of climbing wall. And actually she showed that she likes to climb even in our apartment. So she she’s climbing on all kinds of things like on our furniture. And then she also likes to climb like on the grates that we use to separate her from where we are occasionally, like the kitchen. She will be a climber when she grows up.

Peter O’Toole (25:50):
It’s fun times. Finding time to socialize with your team much more difficult, which changes the dynamics a little, but, and actually as your team mature as well, they, they find themselves in a similar position.

Hari Shroff (26:06):
Yeah. I mean, I think, you know, one of the biggest changes for me with respect to the team dynamic is just appreciating people in my lab that have kids what they have to do. Right. I mean, that’s something that you kind of understand as the abstract and the abstract, but at least for me, like having a kid myself really prove that home. Right. And it’s not easy. I mean, to, to maintain any semblance of work life balance, like with your family. And so I do have more respect for that, um being a dad, myself.

Peter O’Toole (26:33):
So, which is, which is good. I mean, how large is your team now?

Hari Shroff (26:38):
So in my lab in particular, there may be between 8 and 10 people, depending on how you count, but then I also supervise a trans NIH imaging facility, which is kind of like a core facility with just a few staff scientists. And the idea is that they try and deploy advanced instruments that I like home built instruments that people in my lab and other PIs at NIH build, they try it and people in this core facility to try and make that more accessible. So there are three people in that facility as well. So when you count them, it’s more like 13 people

Peter O’Toole (27:11):
So those three will probably have a very different mindset over the post docs that are doing the research side. Cause it’s, it’s no less of a job technically, but it’s a very different mindset. Cause now I guess they’re interacting with lots of biologists and trying to share and spread their expertise and use their expertise to develop lots of applications rather than use, specializing in one area and just building that one bespoke. Have you, how’d you find the differences in personalities between those two?

Hari Shroff (27:42):
Yeah. I mean, I think you’re, you know, you’re, you’re absolutely right, right. So there’s on the one hand they’re very technical diving into, in my case, like what makes a microscope better? So thinking carefully about like what, what breaks microscopes, because you will never find a microscope that is not defeated by a sample. So I think the interaction with biologists is critical for that aspect. Also it feeds back into the technical aspects. And in fact, I love it when biologists come to use the microscopes, like in my lab. As you say, though, like a core facility manager is going to be more interested maybe with making a biological experiment work. And I have immense respect for that because, you know, I, I view this as kind of a continuum, right? I mean, you have your instrument developer, but siloing the instrument developer, like, you know, in a space where they never interact with biologists, it’s just totally a mistake.

Hari Shroff (28:30):
Right. Because then they, you know, they invent something which may or may not be useful. And for me, like building things that are useful, it’s kind of the reason that I have a job, right? I, I’m lucky that I have time in my ivory tower where I can think about the physics of a microscope, but to me, if it’s not used by a biologist in the end, I mean, it’s kind of useless at the very end of the process. So I, I, you know, you’re right. Like the mindset is different in a core facility or even in this kind of advanced core facility where they’re trying to disseminate the technology, you know, they really have to be looking at what makes something useful and how to make it more useful. And I, I, I just think that’s so useful. It’s so important, you know, for the instrument developer to kind of see, and to interact with it is a bit of a different mindset though.

Peter O’Toole (29:16):
Yeah. I guess one nice bit is you’ve got a team that is developing impact and another team that is delivering the impact.

Hari Shroff (29:25):
Yeah.

Peter O’Toole (29:25):
Wow. That’s really quite nice to have both set up there and you’re absolutely right. Those new technologies need support because they’re not off the shelf products at that point.

Hari Shroff (29:34):
Yeah. And, and some of them may, some of them may never be off the shelf. Right? We’ve been fortunate that we’ve commercialized some things at NIH, but you know, there are going to be other technologies that are just too difficult to do that. Or maybe there’s not enough of a market.

Peter O’Toole (29:47):
Yeah. And you see quite a lot of startups who actually say that you’re right. They siloed into a room. They think they know what they’re doing from an engineer perspective, they developed something. But at the end, it’s not that useful to the end user. They’ve moved away from what the end user and how they would engage with it. Cause trust me, biologists are very different animals compared to other science spaces. Likewise, the chemist is different to a physicist and so forth. It’s quite difficult. I think to, for them to get an appreciation of that. Just going back, we started talking about your first publication as well, not your first, your latest publication, but what is your favorite publication of all time?

Hari Shroff (30:27):
I, I don’t know if I would say that I have a favorite, but there are, there are maybe a couple that stand out. I mean, one would have to be my first paper as a graduate student, which was rejected three times before it was accepted. And I think that was a valuable learning experience for me for, you know, some of the hassles and difficulty of being an academic. I mean that, that feature, a feature or downside hasn’t gone away. My papers are still rejected all the time, but but, but that was kind of a landmark thing, right. As a first author getting my first paper published and that paper was a bit ahead of its time, but, but actually is being cited more, it was on force sensing making a molecular force sensor using FRET. So that, that was kind of a favorite just because it was my first. And then, you know, a couple of the early papers from my lab too, right, that ended up kind of laying the groundwork like the DiSPIM or the instant SIM [inaudible], as you are kind of, you know, I would consider them important foundational papers from my lab because they built a solid foundation for which other papers kind of landed on top and, you know, you know, again, those papers were published with just a handful of people in the lab. So they’re special for, you know, for that reason.

Peter O’Toole (31:39):
It was interesting, the first one you said that when in fact it was ahead of its time when you published it. So it doesn’t gather many citations early on, if it’s ahead of its time generally and it takes time and then that momentum grows and then it does become more, more published. But as a, if you’re reviewing, if you were being reviewed, they’re going to be looking at your publications and citations are naturally one of the things they quite often look at, I presume it’s the same with yourself. So, how’d you cope with that?

Peter O’Toole (32:05):
It is great work. And now, now you can look back 10 years ago or more and say, look, it really was fantastic. And yet at the time you could be getting heat for not having the citations or the publications not having the impact just because by the very nature, technology takes time to be adopted.

Hari Shroff (32:25):
Yeah. Yeah.

Peter O’Toole (32:26):
And then actually publish, you’re talking, as you said, five years sometimes to get it to publication.

Hari Shroff (32:32):
Yes. I think you’re hitting on one of the most difficult things we have to deal with in academic science, which is measuring impact and, and papers. And and, and, you know, fundamentally I think this arises from the timescale issue that you pointed out, right? That measuring what somebody’s work is worth is something that takes time. It takes time for that to have an impact and to be picked up by other people and frankly used by other scientists. Right. And this is very difficult because promotions and hiring somebody as a PI, I mean, you know, what do they have to look at? You know, somebody once told me that, you know what, like these measures of H index and citation count and where you publish ultimately, you know, have poor correlation or can have poor correlation with the quality of a scientist, but scientists like to count.

Hari Shroff (33:24):
And that’s a problem, right? In a finite time, how do you measure this? I mean, in a perfect world, you would read people’s papers. You would talk to their references. But the problem is that the reviewers have only finite time. And so how do you reconcile these issues? And I think there’s no perfect answer, right? I mean, the advocates of the kind of reading the science would say, well, what are you talking about? Of course you should read every paper. Of course you shouldn’t pay attention to where it’s published and that, you know, being on the other side of it as a reviewer, yes, you should do those things. But it’s extraordinarily hard as a reviewer, right? If you’re looking at two candidates, one who has, you know, many more citations and many more papers in high impact journal, it’s extraordinarily difficult to, to do the right thing, let’s say, right.

Hari Shroff (34:08):
So I just want to acknowledge, this is a tension that you face at every, at every level of your career, right. It’s just hard. There is a pyramid in how you judge scientists and you know, we all just have to be conscious, right? Of these biases that are baked into the system, including the citations, as you mentioned, I mean, I, I don’t have a perfect answer. I mean, when I try and get my postdocs a job, right. I mean, as, as an academic, I, you know, you have a frank conversation and you say that the chance of getting to that one academic job is vanishingly small. It’s just hard. And if, you know, if you want to play that game, of course we will try and publish a paper in the best journal we can for you. I mean, one of the things I try and do is I relinquish corresponding authorship always to the first author on my papers. That’s a small thing I can do, right. Because credit naturally flows upwards. Right. But of course the people that do the work are the people that need the credit. And it’s hard in academia, right. To, to acknowledge the work that is being done by the people that actually do the work.

Peter O’Toole (35:12):
Yeah. I think what’s sad is I think many realize and appreciate what you’re saying. And yet everyone falls back to the status quo of going back to those citations and stuff. I think sometimes see it’s vital to publish. That is without question. Even if it’s not in a top ranked journal, it is, you have to show output, you have to share what you haven’t learned or what you’ve learned that hasn’t worked. Even you, you need to get that out there somehow. Cause we are being paid to do that.

Hari Shroff (35:40):
Yeah. And finite resources. Right. I mean, this is why I think publishing in peer review journals is important for the same reason. Right. I mean, despite the flaws of peer review, I mean, there, there’s something about it that is, you know, over time inherently error correcting, right?

Peter O’Toole (35:54):
Yep. So moving on, it is quite, it’s very serious, almost a depressing subject, really, because we’re not going to change the world on it. So I’m going to ask you some quick fire questions. Okay. So, so it’s one or the other as quick as you can. So tidy or messy?

Hari Shroff (36:11):
Messy.

Peter O’Toole (36:12):
Yeah. I can tell by the whiteboard behind you. Design or design over or function?

Hari Shroff (36:19):
Function.

Peter O’Toole (36:21):
Soccer or American football?

Hari Shroff (36:23):
Soccer.

Peter O’Toole (36:24):
Right. Good man. You’d be absolutely right. Baseball or soccer?

Hari Shroff (36:29):
Soccer. I just want to say that baseball is boring. I mean, I think everybody acknowledges that baseball is boring. Even the baseball players think it’s boring. If you look at them, they’re chewing gum or tobacco.

Peter O’Toole (36:43):
You probably just offended loads of people, but.

Hari Shroff (36:45):
Maybe yeah.

Peter O’Toole (36:46):
Yeah. It’s not my, it’s not my,

Hari Shroff (36:48):
It doesn’t mean it’s not fun to have a beer. And you know, I don’t know eat a snack in the bleachers, but it is boring.

Peter O’Toole (36:56):
Mind you, on saying that I quite like cricket.

Hari Shroff (36:59):
There you go.

Peter O’Toole (37:00):
So, it’s a bit of a technical game is cricket. It’s very tactical. So that’s good from that side. Thinking of not my cup of tea, tea or coffee?

Hari Shroff (37:09):
Ah coffee.

Peter O’Toole (37:11):
Pizza or burger?

Hari Shroff (37:13):
Pizza.

Peter O’Toole (37:13):
Indian or Chinese?

Hari Shroff (37:17):
Indian, but it’s, it’s, it’s tough. I like Chinese food a lot too,

Peter O’Toole (37:20):
What’s it like over in America when, because UK is brilliant for Indian restaurants and Chinese are pretty good. Okay. Go to mainland Eujrope. Really not quite the same. I mean, UK does exceptionally well.

Hari Shroff (37:32):
Yeah. So I would say it’s a strong function of where you happen to live. We’re very lucky that the NIH and its surrounding area is home to many, many immigrants, which is a wonderful thing, including Chinese. And so the Chinese restaurants around NIH are fantastic. I live in DC where there are also good restaurants, but it can be somewhat harder to find kind of authentic food, authentic Chinese food, and same with Indian food.

Peter O’Toole (37:58):
Yeah. I, so actually I’m with you with it, with pizza, Indian, coffee. Well, yeah, definitely, definitely throughout it. So perfect. Perfect answers. Car or bike?

Hari Shroff (38:11):
Say again.

Peter O’Toole (38:11):
Car or bike?

Hari Shroff (38:13):
Oh you know, I prefer to walk when I can I, I, I, I’m using my car now because of COVID to, to drive to NIH. And I, I admire people that cycle on bike. I wish that I could get more into it, but given the choice, I would prefer to walk over either of those,

Speaker 4 (38:36):
That’s fair enough. A book or TV?

Hari Shroff (38:39):
Book.

Peter O’Toole (38:39):
UK or US?

Hari Shroff (38:42):
Ooh. US is having a tough time right now. But I’m a US citizen, so I’m going to have to go with US.

Peter O’Toole (38:51):
Yeah. Boooo. Teasing. So you’re into books, so that was a very unequivocal, definitely books. And what are you reading at the moment?

Hari Shroff (39:01):
Right now I’m reading a book that I would, by an author that I would, I would totally recommend. A very thoughtful scifi author called Ted Chiang. And one of his short stories has been made into a movie called ‘Arrival‘, which was 2016 movie, which is a fantastic movie about aliens arriving. And it’s not actually about aliens, but so I like, I like reading scifi but I also like reading books about science and books about big things that happen in science like molecular biology or fine men. So I, I like both, both science fiction and fiction and nonfiction.

Peter O’Toole (39:39):
Okay. Do you get much time to do much extracurricular reading?

Hari Shroff (39:45):
Usually when the when the baby goes to sleep at around eight o’clock I have a few hours where I’m either doing more research work, science work, or I have time to read.

Peter O’Toole (39:55):
Yeah. And how’d you find balancing that work life side of things?

Hari Shroff (40:00):
I think I’ve just kind of come, come to kind of accept it. I mean, I, in fact, I can’t even remember what the heck I did before I had my baby. I mean, I sometimes wonder what the hell I did with all of my time. I don’t know. Yeah, I mean, I bounce it as best as I can. I mean, you know, gone are the days when I could easily go to the lab on the weekends. I mean, that’s pretty rare. I would say that my work has transitioned to more reading papers and writing an email when I’m back home. It’s just hard, you know, it’s hard to do it. I mean, I’m, especially when our, when our daughter was born, I was tired all the time. And now that her hours are more normal, it’s easier for me. I can snatch a few hours after she’s gone to bed, whether it’s reading or watching the occasional TV show or doing more work catching up at work. But it’s difficult. I would say that sleep is the predominant thing that is difficult. So that’s, that’s why I find that gets sacrificed in favor of work life balance.

Peter O’Toole (40:59):
Yeah. So actually just thinking about the current times, so COVID-19, we’re locked down, I know you were locked down as well. Did that, how did you find the lock down? How did that affect your work life balance? Was it good, bad, indifferent?

Hari Shroff (41:15):
You know forme, um he, you know, in some ways the work life balance hasn’t changed that much because of COVID because I was writing papers and I got reviewed at NIH virtually. So the people that have really suffered on the work end are unfortunately the experimentalists in my lab, right? Those guys have been champions of trying to like milk existing data sets that they can work on remotely, but the time has come for them where they’re really feeling the pinch of not being able to do experiments as far as work life balance, I’m trying to find the silver lining in being able to spend more time with my daughter. Right. I mean, this is kind of a wonderful time because I can go for a walk with her to the dog park. You know, she loves dogs right now in a way that I wouldn’t have been able to do with like a regular lab schedule. So, so there is some silver lining in spite of the COVID. I mean, it’s, it’s occasionally difficult to bounce the time with my wife because our office is our bedroom. So she has a desk and I have a bed at her rocker chair that she used when our baby was small. So that part of it is kind of a little bit uncomfortable and actually do find myself missing coming into the office In the lab,.

Peter O’Toole (42:20):
Which at least you in there today.

Hari Shroff (42:23):
That’s true. Yeah.

Peter O’Toole (42:25):
Not so bad on that side.

Hari Shroff (42:27):
Yeah.

Peter O’Toole (42:28):
So that, that, that’s a difficulty in balancing data and especially with lockdown and having that space, but there’s always a time that’s very difficult in someone’s career. You’re still very young, you know, but hugely successful, but you must have had difficult, difficult periods. So what have you found, what has been most challenging time that you’ve had to overcome?

Hari Shroff (42:50):
It’s I think yeah, so two times come to mind. One as a graduate student. When I, I kind of like went through this transition of like learning that, you know, at the end of the day, like I’m responsible for everything in my PhD and maybe most people that have, you know, that do PhDs have some period of intense misery in their PhD. Mine was realizing that my advisor was just going to leave me to it. So I, I published a paper on this, this force sensor idea early, and then I wanted to apply it to live cells. And I realized I had this sort of daunting realization that what I did to make this force sensor was not going to work in living cells. And my advisor was not going to help me to do this. And he even said as much, you know, he said that his job was to kind of make me transition into basically doing everything myself. And, you know, I thank I, I thank him now, but it was difficult to hear at the time. So that was the closest that I came to kind of an existential crisis. And, you know, in the abstract, I sort of knew, right. That was what a PhD was about. You go to reading about science, like actually really doing the science yourself, even if you fail at doing it. And there were lots of failures, you know, during that time. So that was difficult. And I got through it

Peter O’Toole (44:04):
What sort of supervisor are you then?

Hari Shroff (44:07):
So I what I would say is that I try and let my, at least right now I try and let people have their own failures, but I am kind of obsessed with failure because particularly for the postdocs, this is their career on the line, right. So I want to know what the problems are so that I can help them attack it. Right? Whether it’s finding a plan B or reframing a paper or what, what their research is. So, you know, I would say that I’m highly hands on in the sense that I want to know the details, but I also want my postdocs to get the experience of building things themselves. I mean, where I’m not so good at this is the writing, because I, it’s very difficult for me to not commandeer the writing of a paper. Even now I I have a tendency to start writing drafts well before we have all of the data and maybe that’s, maybe that’s something I need to work on as a PI.

Hari Shroff (45:03):
But, but I also want to make sure that my, my postdocs and graduate students, that I have had this experience of failing a little bit. I think that’s so important that you do your own science and I’ve, I’ve supervised the gamut of people that are highly independent. And, you know, they don’t want me, my input at all, to people on the other end where, you know, they, they need more of me. And I think that’s one of the most difficult things as a PI. That kind of leads me into the second, most difficult period, which is at the end of my postdoc, wondering what to do. I mean, I was a little bit burned out after my postdoc, you know, after doing all this PALM, I was on the one hand fortunate that, you know, there were, there were many institutes that wanted somebody that did PALM, but then I was in the position of not being, not being, you know, wanting to be theIR super resolution person. You know, wanting to do something else.

Hari Shroff (45:53):
I also explored like being part of a company. You know, so I explored a few startups at the end of my postdoc. And what finally convinced me was the conversation I had with somebody who said, you know, why don’t you just try it and see how this PI thing would go and see if you like it? And if it doesn’t work, you can go do something else. So, but that was also kind of like a difficult time. And, you know, as we said, at the beginning of our conversation, the fear, right, of being able to kind of do it via a PI, that was also something that, you know, maybe I shouldn’t be complaining because, you know, I also have the luxury of being able to get a job and be a PI that’s such a fortunate thing, right?

Peter O’Toole (46:33):
Yeah. But you made a success of it. Well and truly.

Hari Shroff (46:37):
Yeah, somehow, yeah.

Peter O’Toole (46:39):
Do you still have a burning issue to maybe try being in a company one day?

Hari Shroff (46:44):
Not right now, you know, every once in a while, like what I, what gives me pause about your question is that I worry about like ideas, about having good ideas and, you know, like, I, I like to do things that are a little bit off the beaten path, if I can, you know, and I, and I like to do things that at least I feel like have some chance of having an impact. And my fear, I guess, would be regressing to some mean thing where lots of other people are doing the same thing that I’m thinking about. So I worry about having good ideas. But every time I think about running out of ideas, something comes up, right. And the latest thing is this massive playground, which is deep learning, right. Which I’m learning a lot about myself. This kind of old technology that has resurged. And right now it seems like there’s an infinity of things one could with that with microscopy, right? If, you know, as a microscopist, if you know the limitations of your microscope, and if you have that, have a healthy skepticism about neural networks and deep learning, the world is you’re oyster right, because you can, you can combine these things in ways that you wouldn’t have thought possible, like a decade ago. So that’s my current playground. I’m very interested in knowing where these technologies break and, and seeing if we can make them better.

Peter O’Toole (47:56):
That’s another good point that you raise is, you know, 10 years ago, this wouldn’t have been possible. I think there’s a lot of things that there’s a lot of things to be revisited. People have had ground breaking ideas and looked at it and it couldn’t, didn’t go anywhere. So they put it to bed. And in some cases they’ve lost it, you know, they’re putting under the bed and mattress and it’s gone and, and you know, there’s a lot of good ideas that could be easily brought back to the table and are now possible. I’m still not convinced that you can still paint a bee’s wing and see the oxygen changes.

Hari Shroff (48:29):
Me too.

Peter O’Toole (48:29):
Sensitivities have improved just as the speed has improved, but I’ve still got my doubts about that one. But again, it’s things like that suddenly are now possible or potentially now possible.

Hari Shroff (48:40):
Yeah, exactly. And so my advice to, you know, all the scientists I listen to is if you don’t already write down your ideas, because even if you never look at your lab notebook, the action of, at least for me writing the idea helps it stick. And as you say, you know, there, there have been times, a few times that I can think of in my, in my career, my admittedly short career, where an idea that I had a few years ago, which wasn’t feasible, then it would have been like a junkie idea has come back for exactly the reason. You know, you, you say Peter, I mean, we’re, we’re kind of in this unprecedented time where technology is improving all the time. Right? So something can be possible in one area that makes it possible. And you know, an idea in another area that wouldn’t have been feasible a few years ago. So it’s good to pay attention to that. Absolutely.

Peter O’Toole (49:26):
Which maybe actually, one of the first thing you said, when you started your job is to go and have lunch with all the different academic leads, because it’s important to have those contacts. Cause they, they, they will be aware of possibilities or developments that you won’t be, it’s bringing that together. I say your latest publication, it’s got expertise from all over the world coming together.

Hari Shroff (49:47):
Yes.

Peter O’Toole (49:48):
We can’t do it all alone.

Hari Shroff (49:50):
Yeah, exactly. Nobody has all the answers all the time. Can’t do it alone.

Peter O’Toole (49:56):
Talking of answers. Another picture which you sent, which is intriguing. I presume you are the person in the middle here.

Hari Shroff (50:04):
Yes, yes, exactly. That was in Iceland. So Iceland is fantastic country. I mean, I would highly urge everybody to visit if you have the chance when the, you know, when you can, at some point, but one of the amazing things about it is that it’s kind of geothermal. And so they have all of these vents and geysers, in fact, the word geyser came from Iceland. So this is like in one of these areas where I was very cold, I think outside, but there was hot air steaming from the ground, like a geothermal energy park in Iceland. And so I was just standing in the middle of that rising hot air as it came off from a fissure in the ground.

Peter O’Toole (50:42):
So did you do lot of traveling or was it a lot of traveling obviously up until now?

Hari Shroff (50:48):
Yes, I, I, I, I love to travel. I’ve been to, you know, close to, I lost count maybe 40 plus countries. So I, I love to to go and see the world. And this was one, one of the vacations a couple of years before we had our daughter that my wife and I took, driving a car across Iceland, which you can actually do in about a week given how small that country is and how good the roads are.

Peter O’Toole (51:11):
And this one,

Hari Shroff (51:12):
This one was sort of our baby moon, right? It was a vacation right before my wife could no longer travel in Acadia National Park in Maine, which is also definitely a recommendation. It’s beautiful there. So this is on a little island called Mount Desert Island. And we’re looking, looking over woods into the ocean, lots of other little islands.

Peter O’Toole (51:36):
That’s actually, I, I, I travel a lot with work, but actually travelling outside of that, not so often actually. Quite often to the UK and certainly this, this, this, this holiday will definitely be in the UK. We’re not going outside. Unnecessary, I think UK has got some great places. I’m not saying we’re going to Birmingham though. I said, it’s good, but maybe it’s not quite up to spend a holiday there. That’s for sure.

Hari Shroff (52:04):
Not quite that good.

Peter O’Toole (52:04):
You said you traveled across there in a week, but you also when you took your job at Janelia, did you not, you drove your car across the country, didn’t you? Which was a

Hari Shroff (52:14):
Yeah. Yeah. So between my PhD and Janelia, I I bought my car, which I still use today, a 2006 Prius. And I drove it across the country with my dad, from Seattle, where my parents live to Virginia, where Janelia is. But even, maybe even, even more crazy story than that. So like I said, I was burned out after my postdoc and I needed a break before I started my PI position at NIH. And so I bought a car in Dresden, Europe with some of my friends, scientist friends that I met in Woods Hole at a physiology course. By the way, side note, Woods Hole is an amazing place. Everybody should go and take courses at the MBL. But I bought a car in Dresden and drove it across Europe and Asia, the idea was to try and get to Mongolia. So over three months, approximately I drove across many countries then as part of this, so called Mongol Rally, which people can Google.

Hari Shroff (53:09):
And so I actually ended up getting out of flying back in Azerbaijan, but my friends drove further into Russia and Kazakhstan and eventually sold the car in Russia and drove back from and flew back from Russia. So that was quite a journey as well. And also a great thing to do sort of between careers, right. Between as you have these kind of periods of your time in life. Right? I mean, I would highly recommend people take these breaks. It doesn’t have to be driving across Europe and Asia, but it was a fantastic thing to do at the time.

Peter O’Toole (53:38):
Yeah. So you don’t just drive your team, you drive across the US you drive across Iceland, you drive in the UK.

Hari Shroff (53:42):
Oh yeah, yeah,

Peter O’Toole (53:45):
Definitely a theme going through there. Have you still got the same car?

Hari Shroff (53:50):
I still have the 2006 car. Yeah. We don’t have that many miles on it because we barely drive it.

Peter O’Toole (53:57):
Okay. So you drive, ha, this doesn’t figure. You drive all the way across the country or countries, and yet you’re hardly used

Hari Shroff (54:03):
Different car, different car in Europe and Asia, that was a1994 Opel Astra, which, which, which did surprisingly well across Europe and Asia, I think there was only one servicing we had to do when we broke the muffler of the car. Yeah.

Peter O’Toole (54:19):
Just, just before we end, we’ve, we’ve talked about where your background started, where you got to, where are you heading? What was the big unmet need? What’s the next big thing?

Hari Shroff (54:33):
I, yeah, so, so right now I’m focused a lot on adaptive optics. So I think it’s, it’s sort of a crime that, you know, most of us that we do when we do diffraction limited imaging with a spinning disc confocal, let’s say even through a sample that is much more than one cell thick. We’re not getting the full performance of our microscope because the sample screws up the performance as you go deep. But I don’t think Adaptive Optics or AO as it’s called, is cheap or robust enough to just apply. It hasn’t really taken off. So I would like to try and contribute to that and see if I can make it more, something, one can just insert into a fluorescence microscope. I think there is gains to be, to be had to just get the fraction limited imaging in thicker specimens. Even if you’re not looking in something as thick as a mouse brain, I still think there is room to be had.

Hari Shroff (55:21):
And then sort of, you know, not sort of related is this area of deep learning, right. So I would like to see how far one can push that area in conjunction with microscopy. So to what extent can you improve the resolution of your microscope and how much can you believe it as a result, right. If you have this ground truth data, let’s say in a STED microscope or an expansion microscope, you know, can you, can you actually apply that to a wide field or a confocal or a SIM and boost the resolution? And how far can you go? You know, these questions are really interesting to me because I have kind of a skeptical eye and, you know, whenever I look at a computational reconstruction, so I’m kind of interested for my own lab to figure this out, right? Like where are the break points of these digital technologies?

Hari Shroff (56:09):
I think there’s tremendous room and creativity to be had in merging these different kinds of microscopes. And that’s what, one of the things that I would that I’m pursuing myself in my group. But you know, like you say, I also like to look at ideas that are older, that are decades older in some cases, right? I mean, yeah. Astronomers have been doing adaptive optics and ground based telescopes for a long time. So I think there may be more, we can learn from that. And then, you know, I’m, I’m also, I’m also always interested in talking to probe developers. As somebody said ‘they put the gain in the brain is mostly in the stain’, right. So I think that’s absolutely true. We have to pay attention to the kind of probe development efforts that are being done because that really drives development and fluorescence microscopy as well. So these are some of the things that I’m working on.

Peter O’Toole (56:57):
I guess they all go hand in hand cause you’re then back to sensitivity, if you can improve sensitivity or capture photons, then the probes don’t become so limiting. But if they improve you, everything is a step. If they all go together. And I think actually probably computers and computer speed has been the biggest enabler to be able to compute, to develop, to drive even the microscopes that,

Hari Shroff (57:22):
Exactly, and I think, you know, computing speed is getting faster and cheaper all the time. Right. Whereas microscopy hardware has kind of fixed or, you know, it hasn’t come down like so much. Right. I mean yeah.

Peter O’Toole (57:34):
And Oh, I’ve forgot my last question. Darn it. What’s your favorite technique currently?

Hari Shroff (57:43):
Favorite technique? Well, I mean, I love light sheet microscopy and the kind of plethora of different implementations of it, right. That are all suited to different things. I mean, I think, you know, one thing to remember in fluorescence microscopy is that there is no omniscient microscope, which is why it’s such a playground. You know, for a developer like me, of course, the flip side of that, the caveat is that anybody who tries to convince you that their microscope is the best for all samples is selling you snake oil. So that’s kind of a cautionary note, right? I mean that, that, you know, that, that’s what makes it so fun, I think to, to, to, to work in this, in this field, right?

Peter O’Toole (58:22):
Yeah. It’s a very good point about, there’s no one solution to any thing, there really isn’t, which is

Hari Shroff (58:31):
Pick the tool for the job. Right.?I mean, that’s sort of a key, key thing to think about. Yeah.

Peter O’Toole (58:36):
You know, that’s food for thought. Can you work, can there be a system that could be the magic tool?

Hari Shroff (58:42):
I don’t, I don’t think so.

Peter O’Toole (58:45):
Does everything, the best at every element.

Hari Shroff (58:49):
I would love to be proven wrong, but I don’t think so.

Peter O’Toole (58:53):
No, but that’s today, 10 years time? Come back with that question? Maybe there’ll be something out there. Hari, you’ve been great to talk to.

Hari Shroff (59:04):
No, thank you so much. It’s been so fun. Yeah.

Peter O’Toole (59:05):
Yeah. It’s been brilliant. Good luck with the next big steps.

Hari Shroff (59:10):
Thank you, thanks so much.

Peter O’Toole (59:11):
And your little one’s little steps.

Hari Shroff (59:13):
Yes. True. Yeah, exactly. Little steps are probably the things that I think about the most right now. Yeah. So

Peter O’Toole (59:22):
Hari, thank you very much.

Intro/Outro (59:26):
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.

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