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Intro/Outro (00:00:01):
Welcome to The Microscopists, a Bitesize Bio podcast hosted by Peter O'Toole, sponsored by Zeiss Microscopy. Today on The Microscopists.

Peter O'Toole (00:00:14):
Today on The Microscopists I'm joined by Michael Sheetz, University of Texas Medical branch in Galveston and beyond talking about membrane molecular motors and motility. He also tells us about what exciting new data on cells senescence.

Michael Sheetz (00:00:28):
I hadn't done anything on cells senescence and we were at the time using ultrasound to kill tumor cells, something which we happened upon in the latter days of in Singapore. And so I said, well, try ultrasound on these senescence cells. And he found that the senescence was reversed.

Peter O'Toole (00:00:56):
We discussed how living in different parts of the world made him adapt his hobbies and exercise routines.

Michael Sheetz (00:01:02):
We ended up doing a lot of tennis, but you really had to be out there as the sun came up. I mean, Singapore's on the equator, basically two tenths of a degree off. And so the temperature almost never changes significantly.

Peter O'Toole (00:01:22):
And he leaves us with some great scientific and life advice

Michael Sheetz (00:01:25):
During, approaching those aspects, which you are enthused about and where you can feel like that's what I want to do. And when you start out and try it, you like doing it

Peter O'Toole (00:01:48):
All on this episode of The Microscopists. Hi, I'm Peter O'Toole and welcome to The Microscopists. Today. Today I'm joined by Michael Sheetz of the University of Texas Medical Branch, and I need to slow down so, Michael, how are you today?

Michael Sheetz (00:02:08):
Fine. Thank you.

Peter O'Toole (00:02:09):
Mike, thank you for joining me today. I've gotta say there's some guests that you think of and there's some guests you wait on and you've been an inspiration to me since my PhD days. And actually I, I was studying spectrum and spectrum lipid interactions and the diffusion of the membrane through the sites skeleton mm-hmm and you know, last night I thought, come on, I know I've got Mike's work cited in my my thesis. And actually I, I, I went, I, I found my thesis, which was a challenge, and I managed to find a couple of your publications. It was sited within it. Wonderful. Ah, actually look at it. I think it was glyco four a with the nano

Michael Sheetz (00:02:54):
We were actually measuring band three diffusion which is the ani and channel in the red Boxville. Yep.

Peter O'Toole (00:03:02):
Which your of course spectra also anchors or anchored too?

Michael Sheetz (00:03:06):
Well, a portion of it is attached indirectly to spectrum, but the majority of it is freely diffusing

Peter O'Toole (00:03:19):
And that, that, yeah, that was a large part of the thesis. And the Part of looking at the, see how, I guess, to look at how the protein was also limiting diffusion, not because of binding necessarily, but indirect lipid interactions and how that could.

Michael Sheetz (00:03:38):
I mean, it it's been followed up by a number of people Kasumi and others to look at the diffusion within the corral. So in other words, that spectrum binds to the membrane and because it's a long essentially fibrous protein, it can form a corral or an enclosed area of the plasma membrane. And within that, the band three will diffuse, but it won't go over long distances. And so if you have, and he's looked at this with essentially super resolution microscopy and you see the diffusion in the, the corral, but not between corrals. So,

Peter O'Toole (00:04:34):
And that this, I guess these are the days when super resolution wasn't termed either and doing single partical contracting. So I was with Richard Cherry at the time.

Michael Sheetz (00:04:45):
Oh, okay. Sure. I know, remember Richard. Yes.

Peter O'Toole (00:04:48):
Yeah. So it's yeah, it was, it was good times PhD days, but anyway, actually, when, when would you say it was the best time in your career?

Michael Sheetz (00:04:59):
Well, I have to say that the recent work that we're doing has really excited me since we've come, since I've moved to Galveston, a new postdoc came into the lab who had been studying senescence, and I hadn't done anything on cells senescence. And we were at the time using ultrasound to kill tumor cells, something which we happened upon in the latter days in Singapore. And so I said, well, try ultrasound on these senescence cells. And he found that the senescence was reversed and the cells would now grow, lose the other phenotypes associated with senescence, the beta galactosidase expression secretion of let's see senescence associated secretory products and the shrunk in size. So we've been playing with this a lot. We took it to mice and in aged mice who are 22 to 24 months old, their lifespan is two years. They become rejuvenated their physical performance on treadmill and a inverted clean assay is significantly improved by simply an half hour treatment with ultrasound every third day for a month. So this has a lot of implications. We can take mesencgymal stem cells, expand them well beyond what is the APH limit or the normal replication limit, and they will still differentiate properly. So it seems that this way of rejuvenation is harmless and will enable us to do a variety of interesting things. We're do applying for clinical trials to look at diabetic foot ulcers, and soon we'll do whole body treatments to see if the humans behave similar to the mice.

Peter O'Toole (00:07:45):
That answers my next question, whether it was targeted or whole body. And it sounds like currently it's targeted

Michael Sheetz (00:07:51):
Right with the mice. They are put in a bath above the generator and move around in that ultrasound field. They need to be wet for the ultrasound to penetrate their body, but we're using low frequency ultrasound, which doesn't cause heating and which will penetrate the whole human body even bones to an extent. And so we're really excited about the possible implications of this in terms of clinical trials and downstream applications to humans. So

Peter O'Toole (00:08:39):
That's interesting. It sounds great, but the thought of my swimming pool getting busier is this is one of the benefits you could have at the same time. I, I busy enough as it is so that's so, so, so right now is probably the most exciting time of your career, which is I think amazing cause your career has been hugely illustrious over the time. And I, I guess so I, I know you from your, your membrane diffusion and lipid diffusion type work, but of course you are also on the joint discoveries of kinesin,

Michael Sheetz (00:09:12):
Right?

Peter O'Toole (00:09:13):
Which, which is fundamentally vital and looking at the Mesen movements as well at, at nanometer precision lucky or inspired, or how, how to, to be honest,

Michael Sheetz (00:09:30):
I'd describe it as a a random walk indeed which I guess implies luck. I mean, the latest results I was just talking about were occasioned by hiring a new postdoc. We had the ultrasound around, I told him to take the senescence cells and put them on there and see what happens. And he got this remarkable result. You know, these are not things that you planned beforehand but you notice something unusual and it's those unusual quote unquote unexpected results, which often turn out to be the most significant and, and important to follow up on. So my career isn't has not led a linear path. It's been sort of a, a random walk itself. We moved on from membranes to motors and moved from there to integrins and adhesions. And so motility in that regard move from there to rigidity sensing and the rigidity sensor, it seems as we describe it, it's an early activity of the sales pinching, the matrix and thereby measuring the rigidity of the matrix. They pull to a constant distance and then the force is proportional to the rigidity. And that activity is missing in virtually all the tumor cells that we have looked at. And when we stretch those tumor cells, unlike normal cells, which can grow on soft surfaces when you stretch them, the tumor cells on soft surfaces die, when you stretch them. And that led us to ultrasound, which, you know, then led us to looking at aging. So

Peter O'Toole (00:11:41):
, so you say your career's been a random war. It's been very bio orientated from the start. If I take you back to when you were a child, maybe 10, 12 at that point, what did you want to be at that point as a career?

Michael Sheetz (00:11:56):
Well, I grew up in my dad was a, a chemist. Okay. And I grew up in Midland, Michigan, which is the home of Dow chemical company. And so I was influenced by science a lot. At that age I was let's see into was interested in mathematics as well as chemistry and science in general. So and it, it was a science family. So it naturally led to that,

Peter O'Toole (00:12:35):
But, but that sounds more chemistry orientated than, than biology or biochemistry by physics.

Michael Sheetz (00:12:43):
Sure. when I was you know senior in high school, my parents wanted me to go on to medical school and tried to convince me through my college career, that medical school was the important thing to do. My dad philosophized about things and said that, you know, he worked for Dow and he developed these products. It took five to 10 years to get those products to market. And so there was a lot of very delayed gratification. I said, well, you know, you, your doctor, you treat the patient. The patient gets well often right away with the drug that you give them and you get instant gratification. So it's, you know, much more gratifying to be a doctor than it is to be a, a chemist in industrial chemist. Okay. So and from my own point of view, I, I went and served one summer as in in the hospital as in orderly. And that sort of convinced me that the MDs don't know what they were doing, but it worked type of issue. Yeah. And that really, the basis was much more in the biochemistry and so forth. And I decided to take that route and have not regretted it, let's put it that way. So,

Peter O'Toole (00:14:26):
And if you look at your current research of all the research, the impact may be not immediate. You don't get that gratification.

Michael Sheetz (00:14:36):
Right.

Peter O'Toole (00:14:37):
But every Dr. May be able to use it. Whereas before you're being one doctor using someone else, but you are creating the impact, potential is much greater. I would argue what you're doing now.

Michael Sheetz (00:14:49):
Well I, I feel that likewise, I mean, it's a matter that you know, if you wanna make a change in the system, it's not going to be on the day to day basis and doing things in the system. It's by taking a look at the fundamental issues. And then when we get a better fundamental understanding it's easier to make some major changes. I mean, from our point of view, the, I went over to Singapore to set up this mechanical biology Institute there. And we had been doing a lot of work on sort of the mechanical aspects of cells. And it was clear that we knew very little of what that really meant. Okay. The argument that I make is that 30 micron or 40 micron cells create the total form of the organism and they do. So reproducibly in almost a deterministic fashion. You look at these birds of paradise, for example, and, you know, two of those birds look extremely similar. And yet all of the events that led to their formation were performed by isothermal diffusion in the cells that formed them. So those cells must have a means of knowing where they are in the overall body plan and what they must do to create the proper shape of the, or

Peter O'Toole (00:16:56):
I, I, I, I've lost my train of thought there, cause obviously you're just taking it to a different direction just while I was going with it. So, you know, so you are, I guess question, I quite often ask is where you want to be as a child. We've got there and you've gone through, and I think, I think I know the answer already today. Do you wish you'd ever done a different career to what you've chosen?

Michael Sheetz (00:17:22):
Honestly, no. I mean, it, there were days when things did not work and where one felt that you know was I ever going to accomplish anything that was significant and so forth. But in the end, you know, I'm very happy and feel very lucky and fortunate to have gone down this path. Okay.

Peter O'Toole (00:17:52):
And it's,

Michael Sheetz (00:17:52):
And I wouldn't have known how to do that beforehand.

Peter O'Toole (00:17:56):
Let's say it has not only has your research been sort of a wondering path, but your, where, where you've actually worked has also moved between different places you haven't been. And some people do their postgraduate and then they move somewhere and they stay somewhere for a long, long time, but actually you've had quite some quite big changes and quite big influences to, to the different places you've been. I, I think if I facts are right, I don't usually do much research. I did do a little bit that you are at Duke to the university medical school and the chair of cell biology there for 10 years were obviously some of the publications I was looking at were from you dang Columbia. Was it Columbia university before or after that?

Michael Sheetz (00:18:44):
After that,

Peter O'Toole (00:18:45):
After that. And then of course you mentioned you then went to us, so you National University of Singapore,

Michael Sheetz (00:18:53):
Right.

Peter O'Toole (00:18:54):
Set up the new Mechanical Biology Institute. Can I ask this, where is your favorite place to work?

Michael Sheetz (00:19:05):
The place which I felt was best organized for research was Washington University in St. Louis, where I worked before going to Duke. Okay. I was only there for five years, but it was an extremely well run university. And it was in an essence run run by the departmental chairs who appointed the Dean annually, often the Dean stayed on, but he was serving at the request of the chairs. So yeah, that it was no nonsense. They had, you know, online ordering, this is now 85 to 90 well before other institutions, et cetera, et cetera.

Peter O'Toole (00:20:01):
But did, did you learn many tricks from that? When you went over to Singapore to set up the Institute?

Michael Sheetz (00:20:08):
Well, the Singapore Institute was set up with the idea of providing central services and an open lab environment. And we had funds to have lab mothers, so to speak who saw that you know, all the basics were ordered that people didn't get unruly and that the, you know, local lab squabbles were settled, et cetera, et cetera. And because it was an open lab situation there was a lot of communication. So any technological developments were rapidly shared and it was a, a really great environment.

Peter O'Toole (00:21:07):
And did you find any, so how did your research go with that? Cause there's a lot of effort setting that up. Was the infrastructure leading it mm-hmm did your research keep going well at that time?

Michael Sheetz (00:21:18):
Yeah. I mean, it, it went fine because the, my job was to, you know, sort of see that once this was set up, it would continue to run well. And that was an administrative duty that took maybe 20 to 30% of one's time. The rest of the time though, was devoted to supporting the students in postdocs.

Peter O'Toole (00:21:48):
And you sent me one picture which is you actually in the lab, right. How often do you get in the lab?

Michael Sheetz (00:21:58):
Well less now, obviously than in the past. I worked at the bench you know, up until the time I moved to St. Louis. and then after that I was departmental chair. So those administrative duties sort of precluded my own lab time. Okay.

Peter O'Toole (00:22:23):
It looks like a very organized lab as well. Just looking at all the bottles that are nicely lined up behind.

Michael Sheetz (00:22:31):
Well, yeah, this yeah, I can't say that all the people in my lab were so organized. Let's put it that way. and so I, I don't let's say enforce order in the lab, that's pretty much less a fair and if the person succeeds in my lab, they will usually succeed elsewhere. So that's, that's certainly been a rule of thumb.

Peter O'Toole (00:23:06):
And what, what was it like moving from the us to Singapore were there big challenges with that?

Michael Sheetz (00:23:14):
In a sense, no, because they, we had sort of elevated status there. And so once we hired these people to, in essence do the day to day lab work and do the ordering and so forth my position was really to see that good science was being done and that, that we brought in, you know, good speakers for example, and that we, we recruited good people. And so all of that could go on just fine. And the labs were running well.

Peter O'Toole (00:24:03):
Yeah. And, but what about outside of the lab? Because I, the climate is different. I, I, I've only been to Singapore once, actually over to into the US side, actually with a, oh, there's, Zeiss meeting over there. I talking about the, Airyscan,great some years ago. And I, I certainly remember the weather going from hot to the most torrential downpours,and the amazing infrastructure, the roads just dried up and just where the water went. It just sheds the water really fast, but that must have been again, something different, just, yeah. You are more limited in what you can do activity wise.

Michael Sheetz (00:24:48):
Well, yeah, I mean, my li wife and I both like to do exercise every day and over there we ended up doing a lot of tennis, but you really had to be out there as the sun came up. I mean, Singapore's on the equator, basically two tenths of a degree off. And so the temperature almost never changes significantly. And the day span, daylight hours, don't change. Sun comes up at seven, goes down at sevens on eternal daylight savings time. And so you wanna be out on the tennis courts at seven o'clock and then by eight 30 or so after you've shed two to four pounds of, of water you go back and rehydrate. So that's, that's basic routine.

Peter O'Toole (00:25:49):
Are you still keeping up the tennis now be you back in the US?

Michael Sheetz (00:25:52):
Yeah, yeah.

Peter O'Toole (00:25:54):
Yeah. And over there, I, I, I noticed your mug that you were drinking from early, before we started had some birds on it. So he is birding another part of your hobbies.

Michael Sheetz (00:26:07):
Yeah, well, my wife is a, a big birder and so after we got together, you know, going out I didn't really like the binoculars, just looking at the birds and decided I was interested in photography more and so bought a large lens. And we went on safari as well as to Papa new Guinea. And it was a lot of fun just really trying to capture the birds in various poses, et cetera. So that's been a big pleasure

Peter O'Toole (00:26:48):
It's, it's not the easier to task. So just I've, I've I Digiscope a little bit or been known to Digiscope quite a lot in the past. I I've gotta ask, having just recently got through a ton of pictures, how do you choose which ones to keep and which ones to delete and how efficient are you at doing that?

Michael Sheetz (00:27:07):
I'm not all that efficient. I mean, it's it's a creative process in that often if you, the picture fits the criteria being in focus then you have the issue of color adjustment and cropping and so forth that come into play. I ran into at one point a national geographic photographer who gave me the, the one third rule, which is that the bird should not be in the center of the photo, but should be essentially one third off and all, you know, in facing in the larger direction. Okay. And so that, that's a very helpful tool and you know, you try to do everything along that line. And I really enjoy the editing of the photos. I get started on that process in its one, which often takes more time than I had allotted for it type of thing

Peter O'Toole (00:28:25):
Is that Photoshop you're using for that

Michael Sheetz (00:28:28):
Light room.

Peter O'Toole (00:28:30):
Okay.

Michael Sheetz (00:28:31):
But I mean, it, it goes back to the issue with students of them trying to choose an area to go into. And I often emphasize with them that you wanna go into those areas where you are enthused, where, you know, you want to go and do that work. And often that the work once you're absorbed in it, other things fall away. So rather than, you know, constantly looking at your watch, wondering when, when will this be over and when can I leave, you know, type of situation. So and I think that's important for, for people,

Peter O'Toole (00:29:20):
As long as it's only the your bird photos that you are editing and not the the scientific, the microscope images that you're requiring that, that, that you are editing. Have to remember the one third rule though, I guess we are framing ourselves on the microscope. Maybe it's just make sure the cell of interest is always one third to the side,

Michael Sheetz (00:29:42):
Something like that. I mean, particularly if the person is looking the other way, so the eye tends to go where the person is looking. Let's put that

Peter O'Toole (00:29:53):
And think, thinking back to the microscopy obviously a lot of your early, early studies were very heavily micro. What, what is your favorite microscope technique?

Michael Sheetz (00:30:07):
I mean, the one that I find very dynamic and one which has fallen out of favor is video enhanced differential interference contrast. Okay. Which enables one to monitor objects moving within the cell and you get a real feel for how dynamic the cytoplasm is under those circumstances. Using super resolution, we invested heavily in super resolution microscopes when we started the Institute in Singapore, but it was really only toward the end of the time there in 2018, 2019 when people really started using super resolution.

Peter O'Toole (00:31:06):
Okay.

Michael Sheetz (00:31:08):
And the problems had to, you know, grow to that level. Okay. And once you understood basics, then you wanna know the details of what's in this complex how might it be moving and how dynamic is it, and super resolution microscopy can help solve a lot of those problems. So

Peter O'Toole (00:31:32):
Would you say it was just waiting for the question to grow into the technology, or do you think also the fact that I think a lot of the commercial companies made the technology far more accessible to a non-specialist MICR to be able to use, to solve their biological questions?

Michael Sheetz (00:31:48):
Well, I think it, the, you know, I'm a great believer in hypothesis driven science. And so indeed the ability to see things in the light microscope at the level of let's say doing video, I mean super resolution, confocal microscopy gives you about a hundred nanometer resolution. And so that's the size of a lot of the smaller vesicles and larger protein complexes. So you can, you know, hope to follow those movements in real time and understand in a physiological environment what is going on. So and that, I think raises a lot of questions, enables one to really take hypotheses about how this is actually functioning and to prove or disprove those ideas.

Peter O'Toole (00:33:11):
I, I, I, I love the the favorite technique that you had. I, I've got to say certainly from back watching some of your early work, FRAPP was certainly one of my favorite techniques for looking at sort of the diffusion side of things. Mm-Hmm, some quick fire questions for you. Would you say you were in night Owl or an early bird?

Michael Sheetz (00:33:34):
Now I've been, become an early bird because, you know, I'm in Galveston, which has a, a climate at least right now, very similar to Singapore. It does have winter, and we've been through a freeze here, but most of the year or six months plus of the year, it's quite hot. So I've become an early birdie the old days. When I was in the lab, I was often working at night, did most of my thesis work from, you know, eight o'clock on and would often not get home until one or two in the morning. So

Peter O'Toole (00:34:18):
They were long stints. But didn't surprise me. So you still playing tennis first thing in the morning then?

Michael Sheetz (00:34:24):
Oh, I, I only took up tennis because my wife was interested in it. So,

Peter O'Toole (00:34:32):
So what did you do before you said you're always being keen on keeping fit exercises?

Michael Sheetz (00:34:36):
Well, mostly running used to run quite a bit every other day, at least back in, in Duke and before.

Peter O'Toole (00:34:49):
And what was your distance?

Michael Sheetz (00:34:52):
Oh, typically three to four miles three to five miles, depending on the type of thing.

Peter O'Toole (00:35:00):
So between the 5k and 10 K sort of distances. Okay. PC or Mac

Michael Sheetz (00:35:08):
Mac the whole time.

Peter O'Toole (00:35:10):
Okay. Mcdonald's or burger king

Michael Sheetz (00:35:14):
Well, haven't been the, one of those that I've been to most recently is burger king because they have the impossible burger Whopper.

Peter O'Toole (00:35:28):
What on earth is that,

Michael Sheetz (00:35:30):
Well remember an impossible burger is a plant based product. It's basically yeast derived developed by a chemist at Stanford who found out what gives rise to the meat taste. And then expressed those necessary proteins and so forth in yeast. And those yeast now give the flavor to the burger.

Peter O'Toole (00:36:06):
How was it?

Michael Sheetz (00:36:08):
Oh, it's good. Yeah. We have a hard time differentiating it from standard meat burger.

Peter O'Toole (00:36:17):
Now I'm gonna gonna have to go and try a burger king aren't I. Not tonight though. That's for sure. Okay. Tea or coffee,

Michael Sheetz (00:36:27):
Coffee.

Michael Sheetz (00:36:30):
First thing in the morning, you know, I, I normally end up having on the order of four or five cups a day,

Peter O'Toole (00:36:41):
Are they sort of long black, white espressos

Michael Sheetz (00:36:47):
Espresso derived, and then sometimes I'll, I'll put milk in it, but it doesn't matter much anymore. I can, I can take stuff

Peter O'Toole (00:36:59):
It's caffeine. Beer or wine,

Michael Sheetz (00:37:04):
Wine preferably yeah,

Peter O'Toole (00:37:06):
Red or white

Michael Sheetz (00:37:09):
Red, so,

Peter O'Toole (00:37:11):
And chocolate or cheese.

Michael Sheetz (00:37:16):
Both actually I do wanna avoid high blood pressure and so forth. So tend more toward you know, a lighter aspect of that and often crackers with hummus and things instead of the cheese,

Peter O'Toole (00:37:41):
Singapore were USA,

Michael Sheetz (00:37:43):
Pardon

Peter O'Toole (00:37:45):
Singapore or USA

Michael Sheetz (00:37:48):
USA. I'm an American for a long time. I mean, Singapore is a lovely place. They did very well by us. We could, we set up the Institute there and we wouldn't have been able to do that in the US. We had the money to do it right. The people we hired over there were extremely good dedicated and kept that place running. I mean, I had only in 10 years, a handful of personal situations that I had to get involved with. So that, that meant that everything was pretty well buffered and pretty well run over there that said it's a boring place. And it's major attribute from my point of view is the airport, which is outstanding. And you are there two hours to, most of Southeast Asia, four hours to India, China and Australia. Yeah. So it's easy to get around

Peter O'Toole (00:39:10):
And, and a great scientific environment

Michael Sheetz (00:39:12):
And a great scientific environment. A lot of people who travel to the far east will go through Singapore. And so we had no trouble getting good speakers and so forth over there. So,

Peter O'Toole (00:39:26):
So I, I will come back to the quick fire questions in a minute, because you, you mentioned about, you had very few problems when you were over there, when has been the most challenging or difficult time of your career?

Michael Sheetz (00:39:41):
I would say that my move from Duke to Columbia was challenging. People who were recruited to duke, it's a rural environment. Life is easy in the south da, da, da, da and moving to New York is quite the opposite. It's huge, huge metropolitan area. People with kids don't wanna move their et cetera, et cetera. So I basically set up my lab by myself there. I didn't have a crew that came with me that helped set it up, set it up. So that was challenging.

Peter O'Toole (00:40:34):
And did you appreciate that, that would be the case when you accept a job at Columbia University or it, was that something that only once you'd accepted you went, oh, okay. This is not gonna be quite as easy as I thought.

Michael Sheetz (00:40:46):
Well, I mean, it was largely personal reasons that caused me to move. And so, you know, you accept that,

Peter O'Toole (00:40:56):
But no regrets.

Michael Sheetz (00:40:59):
I mean, we, I was able to recruit a very good cadre of, of people there better than I, I, you know, could recruit at Duke. And so things went very well.

Peter O'Toole (00:41:16):
So it did have its plus, so, so you'll notice it's difficult in who you are recruiting what the recruits were very, so it does have its plus points, its positives.

Michael Sheetz (00:41:24):
Right Right. Very much so. Yeah. Which is

Peter O'Toole (00:41:27):
Good. So thinking of good times as well. What about your favorite publication that you've either authored or co-authored?

Michael Sheetz (00:41:37):
Oh well, it's it's hard. I mean the, to, because we've been in so many different areas in each has its own, you know essence I mean we had the initial paper in the red blood cell area where we took the spectrum deficient mouse, erythrocytes, and found that diffusion occurred there just fine. Whereas you know, Cherry, your advisor had measured the rotary diffusion of band three. Yep. And it was the same with, or without spectrum, but the lateral diffusion of spectrum was very dependent. Letter diffusion of band three was very dependent upon spectrum.

Peter O'Toole (00:42:40):
I was transient dichos and wasn't it. I think he used for that rotational diffusion. I remember that rig very, very specialist.

Michael Sheetz (00:42:48):
Right. And then working with Ron Vale and Bruce Schnapp and Tom Reese we discovered the kinesin motor and that was you know, a lot of fun. And the the anecdotal story there is that we had put in a paper to saying that it was a, a membrane channel possibly similar to the flagella rotor or system, because what we saw was at the same vesicle was able to move in essence in two directions on the microtubules. So and there with the bacteria flagella rotor, it can change direction quite easily. The paper was reviewed and we had a, a number of little things to take care of to resubmit it. And then I was working with Ron Vale late one night in the lab, and he was trying to reconstitute the vesicles with the microtubules and with some supernatant to see if we could reconstitute the vesicle movements. Yeah. And we noted that the vesicle prep that night just didn't work. So we had almost no vesicles, just microtubules and supernatant, and the microtubules were attaching to the glass and moving, which indicated that the motor was in the supernatant and that was causing the micro tubal to move on the glass something which our competitor, Bob Allen had noted before, but had a totally different explanation for it. So using that micro tubal movement assay we went on to purify kinesin then from both the squid system and from bovine brain and it was off to the races,

Peter O'Toole (00:45:21):
But I can finally, finally, kinesia must have been one of those moments when you, when you see you find it, you prove it as quite a moment that you remember, I presume you remember where you were, where in the lab or the office exactly. That moment.

Michael Sheetz (00:45:35):
Right, right. We were working, this was like 1230 at night. And you know, my first words were, oh shit. Because the paper that we had submitted was all bullshit at that point. And so we never resubmitted that paper, but

Peter O'Toole (00:45:56):
now what, what, what a moment, what do you think it was a good time to be a scientist a bio chemist at that point for discovery, you know, oh, there's so many unknown still out there for young Bio chemists coming through to discover, do you think, or, you know, was it a really good time to be in that position?

Michael Sheetz (00:46:21):
I mean, certainly we had a wonderful time really trying to address motility questions that had not been addressed except by a few people in biochemistry, the biochemists were focused on metabolism proteins and cell biologists looking at the cytoskeleton and so forth. But these dynamic questions were much more difficult to address. Okay. I think likewise, nowadays the issue of the problems that I raised in mechanical biology are really daunting in terms of understanding how diffusive motions and basic diffusion processes can be harnessed by a cell to create a essentially deterministic behavior. So and we have a lot to learn there.

Peter O'Toole (00:47:32):
Yeah. And I, I, if you think about it, you have the hypothesis, you can test it. It's difficult. There's not, I don't think there's ever that moment of clarity. There's always gonna be an interpretation in that area,

Michael Sheetz (00:47:48):
Right.

Peter O'Toole (00:47:49):
That, that maybe takes some of that that, that, that moment of joy, it becomes a, a prolonged moment of joy that you never end of.

Michael Sheetz (00:48:01):
Right. That's when things are, are simple and we don't know a lot, then a simple concept of, of let's say a motor is something that is quite remarkable. I would say the you know, in the recent past the Dowda and others with CRISPR CAS9 was you know, a major fundamental change in our, our understanding. Okay. So and otherwise, however we know all the components, and so you can't just take a motor and say that, you know, this is fundamentally blah, blah, blah. And really the thing, because you know that there are, you know, 30 other motors there. And so what becomes the description of them? And that's much more complicated.

Peter O'Toole (00:49:09):
I, I would say without putting anyone off, if you're a young scientist out there thinking this is just sounding harder and harder, but then if we just reflect back to the start of the conversation and Mike, you were talking about your cell work, it's there, isn't it? You know, you still got that, that moment of hallelujah very early on.

Michael Sheetz (00:49:33):
Sure.

Peter O'Toole (00:49:35):
So, so he's there, it's just, just the questions are different and the problems are different, but just as profound.

Michael Sheetz (00:49:42):
Well, I agree. And I think the best way to try to address this is either through following up on those unusual results that you hadn't expected. Okay. Because you formulated a model on what you know, and if something doesn't work, it comes up with a totally different answer. You throw out that hypothesis and now you try to understand the other the other approach that we've used a lot is to do what I call Friday afternoon or Saturday morning experiment, based upon the literature you say, well, if this happens and that happens, then this should work in this way. And if you have a component of what's needed to an address, that question, and a friend has the other aspect, either a, a bit of machine, you know, tool microscope, et cetera to help address that, then you can put the resources together and come up with a preliminary answer in an afternoon. So and those experiments don't always work. But a lot of our, my career has been following up on those that have worked.

Peter O'Toole (00:51:25):
Would you say more, have failed than succeeded on those right. Afternoon, Saturday morning, you know, just let's yeah. I take it. You you're working with friends and you're thinking actually, why don't we just see what happens if I, if I take my protein, your technology, let's see what happens or combine our study type questions and see if there's anything

Michael Sheetz (00:51:45):
Right.

Peter O'Toole (00:51:45):
Yeah. Combined and basically failed, but then they've been very fun doing

Michael Sheetz (00:51:50):
Right. I mean the, the early on in my career, I was trying to address questions that still have not been addressed. So for example one of my early papers was on how red blood cells became like a kind of sites. The, the projections from the surface which were driven by anionic compounds and singer had the idea. This was like the BI metallic couple you're causing with the ones that went to the outer half of the Bilayer expansion of that half of the Bilayer and thereby causing curvature. And we basically proved that and subsequent studies had followed up on that. Now, in the meantime, when I started my lab, we incubated red blood cells with the compounds that would cause the Akiny to form and low and behold after an hour or so in medium with, with nutrients, they went back to Biconcave discs. And if you washed away the compound they became cymetastatic. They had imagination. So clearly the cell was able to sense that change in curvature or change in mm-hmm half BI layer pressure and had a mechanism biochemically to compensate for that. And it was dependent upon the Pintos phosphate sh blah, blah, but we've never followed up and don't know to this day, how that is sensed, nor how that actually works.

Peter O'Toole (00:53:53):
So now that, so now for advice of anyone starting out, they're somewhere where they could start out. Sure. Going back to of the quick five questions, we don't have a huge amount of time left. What would you say is your favorite co do you have a favorite conference that you go to?

Michael Sheetz (00:54:11):
I mean, I used to go to cell biology quite regularly. The questions that we're trying to address now have, as I say, taken us into the field of aging and so know we're moving to a new set of, of conferences. And you know, when I go back to cell biology, it's usually to catch up with friends and understand what's what's going on there. So,

Peter O'Toole (00:54:43):
Yeah, I, I dunno the senescent feel well, but it always sounds a bit sleepy if it's a senescent field, but , it's just never good way to word it. If you go, so you've been invited speaker many times over what would be the favorite food, so they usually they'll take you out for dinner, you know, as a keynote speaker, what would be the favorite food that they could put in front of you and you think, oh, spot on. That's perfect.

Michael Sheetz (00:55:10):
Well, we certainly enjoy sushi and a lot of the Japanese fair. Okay. And but in Europe, I mean, the food is excellent there in Italy, France, et cetera, is being so,

Peter O'Toole (00:55:29):
So is there any food that actually that is put in front of you thinking, oh, I really wish I didn't have to eat this

Michael Sheetz (00:55:38):
Well, it's, it goes back to I mean, I tend to stay away from purely vegetarian dishes. Although we, we try to be vegetarian a fair amount you know, it, it occasion they drop in my vitamin B12 levels because you get most of your vitamin B12 from meat. So but yeah, I would say and, you know, for that matter, I don't dislike at all meat, you know, in the sense that I grew up with it and putting a steak in front of me is just fine, but it's not something I do regularly.

Peter O'Toole (00:56:31):
Okay.

Michael Sheetz (00:56:33):
I mean, I avoid bad tasting food. Let's put it that way.

Peter O'Toole (00:56:38):
Well, I, I guess that's obvious book or TV.

Michael Sheetz (00:56:46):
I would say unfortunately my wife and I tend to watch the evening news over evening drinks and then segway into one of the mystery or other series that we've been following. So, and I believe that in the future, I'll be reading more. Let's put it that way. I used to read a lot.

Peter O'Toole (00:57:11):
So, so on the misread, on the TV programs, is there anything that you really shouldn't be telling me about that is actually a bit embarrassing, but you're just about to tell me about what is, what is your worst TV scene?

Michael Sheetz (00:57:24):
I mean, we watch a fair amount of Nordic noir.

Peter O'Toole (00:57:28):
Okay.

Michael Sheetz (00:57:31):
And that's, that's something we've gone to, and, and also the there's a series on, we have a second home in Santa Fe and Hillerman novels of mystery novels of, of the Navajos and Indians. There are really quite interesting. So there's now TV series on

Peter O'Toole (00:57:58):
What about your favourite movie

Michael Sheetz (00:58:06):
I mean, the ones that I gravitate to I mean, we've seen I mean the Lawrence of Arabia is one of the best I, I find,

Peter O'Toole (00:58:33):
See that starred me well, no, it's just my namesake. Wasn't it? so, yeah, last, last, I, I, I, I am still alive. I might be original Peter,

Michael Sheetz (00:58:48):
Well to visit Petra and Wadi rum. And those are really wonderful places. So you get the real feel for the place for Lawrence over Arabia, visiting those

Peter O'Toole (00:59:07):
And a very cinematic film as well. Certainly a wide screen viewing. And what about music genre? What sort of music do you like listening to?

Michael Sheetz (00:59:19):
Primarily classical, you know, we often go to like the baroque and Santa Fe has a Baroque festival every year. It's just started, we went to a concert there on Monday night and we'll go back to a number when we return in August. So,

Peter O'Toole (00:59:45):
And we are now coming up almost perfectly to the hour mark. So I've got one other question. Do you have any advice to give to anyone starting out their career?

Michael Sheetz (00:59:57):
I mean, the, this is the thing that we talked about earlier doing, approaching those aspects, which you are enthused about and where you can feel like that's what I wanna do. And when you start out and try it, you like doing it. And, and sometimes what you think you would like to doesn't turn out to be that, you know, what you really get involved in. But if you think about where you gravitate in that sphere in that occupation, some people gravitate toward experiments, others gravitate toward theory you know, follow your body, follow your mind. I should say.

Peter O'Toole (01:00:54):
I think that's a very good advice. And I think if you look back at many of the others, what we podcast, Scott Fraser Ernst Stelzer. So they've, they've certainly had very convoluted roots to where they are today. Even Dan Davis started as a physicist, became an immunologist. I know probably as big as well, known as an author. So it really is follow your passion and what you are good at, I guess, Mike thank you for being such an inspiration, even though you didn't know it during my PhD days. And thank you for joining me today and everyone. Thank for my pleasure. Thank you, Mike, and thank you for everyone who's listened, watched, and please don't forget to subscribe. But Mike, thank you so much. It's been really wonderful to meet you properly.

Michael Sheetz (01:01:35):
Nice meeting you as well. Thank you again. Thank you.

Intro/Outro (01:01:39):
Thank you for listening to The Microscopists, a Bitesizebio podcast sponsored by Zeiss microscopy to view all audio and video recordings from this series, please visit bitesizebio.com/themicroscopist