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Intro/Outro (00:00:02):
Welcome to The Microscopists, a Bitesize Bio podcast hosted by Peter O'Toole, sponsored by Zeiss Microscopy. Today on The Microscopists.

Peter O'Toole (00:00:19):
Today on The Microscopists, I'm joined by Nobel Laureate, Marty Chalfie of Columbia University. And we discussed the importance of perseverance.

Martin Chalfie (00:00:27):
I worked in a lab this summer after my junior year, and it was a disaster. I did experiments all summer and they never worked

Peter O'Toole (00:00:38):
What continues to excite him about his work.

Martin Chalfie (00:00:42):
I get excited about having ideas and having the rare time when those ideas actually work. It's it's really terrific

Peter O'Toole (00:00:51):
Traditions he wished he kept up

Martin Chalfie (00:00:52):
Every time the paper was accepted. I go into his office and he'd take out the bottle of scotch whiskey from his desk and we'd get out the five or 10 ML beakers, the really tiny ones. And we'd have a little beaker sort of toast that they that this was work

Peter O'Toole (00:01:17):
And his dream alternative career,

Martin Chalfie (00:01:20):
I would love to be a professional guitarist, but I'm never going to get to that place. That's

Peter O'Toole (00:01:27):
Well, on this episode of The Microscopists, Hi, I'm Peter O'Toole from the University of York. And today I'm joined by Nobel Laureate, a professor at University of Columbia, Marty Chalfie Marty, how are you today?

Martin Chalfie (00:01:49):
I'm quite good theater. Good to be talking with you.

Peter O'Toole (00:01:53):
I'm gonna ask. You obviously studied back in the UK. When was the last time you were in the UK?

Martin Chalfie (00:01:59):
Well, the last time it was probably five or six years ago, visiting friends. But I, when I was studying there, that was between 77 and 82. So quite a long time ago for that,

Peter O'Toole (00:02:13):
You still do get over.

Martin Chalfie (00:02:14):
Every once in a while, like everyone else not traveling during the pandemic, but looking forward to it in the future,

Peter O'Toole (00:02:25):
Do you miss the UK?

Martin Chalfie (00:02:27):
I do it. It was very interesting living in Cambridge, not only for the science, which was quite wonderful, but it was also because I was in a, I was in an unusual state in the sense that I didn't care about English politics because there was way I didn't care about US politics. So it was sort of apolitical. It was also that I found that my inhibitions went away in certain regards. So I I've always liked folk music, music in general. In the United States, if I went to a concert, I would even a small concert. I would never feel comfortable going and talking to the performer. But I found that when I was in England, those inhibitions went away and that if I listened to something, someone and I liked what they were playing and I wanted to find out more about what they were doing or anything, I went backstage and talked with them. So I found that my inhibitions were well, were certainly different when I was there and I enjoyed that it was liberating to be in another country.

Peter O'Toole (00:03:58):
I I'll come on to the science in a minute, but did those inhibitions return when you went back to the US

Martin Chalfie (00:04:06):
Not entirely but there are, there are other things I I, I view this as a positive, other people may not being away for five years. I lost track of all sports. And so I, when I came back professional sports, other than maybe basketball as something to watch were of absolutely no interest to me. And I, I, so I didn't miss them. It was sort of like taking a vacation from it and then realizing I wasn't as interested in that. So there I, my interests changed as well.

Peter O'Toole (00:04:47):
That, do you not miss that, that distraction?

Martin Chalfie (00:04:52):
I have other distractions. So I know I didn't, I didn't miss that. I think part of this, I there's when I started my lab in 82, I had a number of wonderful people in it. And two of them, one was a postdoc and the other was a glassware washer. We're real fans of the New York Mets baseball team. And a couple of years after the lab started the, this baseball team, the Mets were in the world series. This was very exciting. And these two people were just beside themselves. They were so excited about this. The postdoc as a young girl, had baked cookies for the ballplayers and used to go to the ball field and give them out to the thing. And these people didn't have a lot of money. And so when their team that they had been supporting for their whole lives was in this championship, they announced the team announced we're only selling tickets mainly to the ticket, the, the season ticket holders. So all the pans that couldn't afford, you know, corporate people could afford that, but all the regional fans couldn't afford, they were left out. And that really made me unhappy about, about that, about how they were treated. And then right after they had won the world series, they announced we're going to have all these very expensive boxes for the corporate season ticket holders to have. And so that really, I think maybe more than anything sort of cemented my feeling that I wasn't such a fan of professionals sports, because it was much more a moneymaking enterprise,

Peter O'Toole (00:06:52):
Like thinking, say you went to the UK in 77 and that was at the LMB. So what were you doing before you came to the UK?

Martin Chalfie (00:07:02):
Before that time? I was a graduate student in the physiology department at Harvard working with a wonderful advisor Bob Perlman. And we were studying the, both the secretion and the biosynthesis of catacholamines from what were really tumors of the adrenal gland from rat. So it was basically neurochemistry. And I had worked with him and Bob was really the perfect person for me to do my graduate work with. I so a little bit of the grizzly background when I was in college, I was I was interested in sciences. I majored in biochemistry and I knew that if I wanted to continue on, I had to work in a lab. And I worked in a lab the summer after my junior year. And it was a disaster. I did experiments all summer and they never worked. Everything was failures. And at the the end of the summer, I went to talk with the head of the lab and he said, well, you know, there's a couple of weeks before the term starts, go home, rest up relax, try the experiment. One more time. When you get back, see if after being refreshed, if it works. And I did all this. I came back and was enthusiastic, tried it one more time. It failed completely. And I decided that's the end of science for me. I have proven to myself that I am not a scientist because I can't do experiments. Of course, I never asked for help. I really didn't know what I was doing. I was terribly naïve about the whole thing, but my confidence disappeared. I did a bunch of part-time jobs. And then eventually one of the jobs I got was to be a high school teacher. So for a couple of years of, as a high school teacher, I made a discovery when I was a high school teacher. And that is that high school students have summer vacation, but high school teachers have to find a job over the summer. And a friend suggested a lab at Yale. And I went to work in this lab for the summer. And without going into the details of that, the experiment worked. It was an experiment that I had thought up or wondered about, found somebody to give me the right advice about it. And I got a lot of help from other people, but the experiment worked got me excited enough to apply for graduate school. But I have to say, when I got to graduate school, I didn't have a lot of confidence. I really was unsure about myself. I was excited about being in graduate school, but I wasn't really sure.

Martin Chalfie (00:10:19):
And Bob Perlman was the perfect person to work for. I had a desk right outside his office and his office door was virtually always open. And he tolerated me barging in all the time and telling him ideas or questions or anything. And we have had, we had, and we continue to have a very close relationship. And it was something where we were working on things on a daily basis, hourly basis. And he had this desire that no matter when the experiment work finish nine o'clock, 10, o'clock, 11 o'clock at night, I would call him up and we'd talk about the results and we'd talk about what the next day's experiment would be. So it was this daily reinforcement and interaction. And I feel I really needed that as a beginning scientist. And it gave me a lot of confidence. This is in contrast to my post-doc, which was the Sydney Brenner, Sydney accepted you into his lab, the laboratory molecular biology, and you were on your own. He expected people to be independent and working on their own. That doesn't mean that people didn't talk to one another, and there were lots of interactions. Cause there were, and they were incredibly important, but Sydney and I, maybe I was there for five years. I think we talked about science, maybe five times in those five years, about once a year and many years later, my friend Phil Anderson, who was also a post-doc at the time. And I were comparing notes. And I said to Phil, you know, I talked of Sydney five times in the five years I was there. And Phil said, that's funny. I was there for five years. I talked with him five times in the five years too. And then we simultaneously said to each other, and the longest conversation I had with him was when he had his motorcycle accident and was in a hospital bed. So he couldn't walk away. And this is, we found this to be very funny, but that was also the perfect thing. At that time. It was wonderful saying, realizing. And I think the LMB was really terrific at this. There were great colleagues, there was any equipment you wanted, they would make something. If you didn't have it, there was supply any supply you needed. You had no excuse. You're on your own in the sense that you, you had to be the one to bring up things. And I think that was the right thing to have at that next stage in my development, be able to interact with colleagues to talk things over, but be ultimately responsible entirely for what was going on in which experiments to choose to do and what directions to go and so on. So those to me, I had sort of the benefits of both of these things. I'm not so sure it would have worked in the opposite order, but the way it did work out, I think was really terrific.

Peter O'Toole (00:13:51):
I've got two questions arising from that, that the first one is from not being very confident and not being very sure of yourself, when you came out and you, you came to the UK, that's a giant step persona who says I haven't got much confidence.

Martin Chalfie (00:14:09):
W I, I didn't think I was terrible. I also didn't think I was the best person that was coming there. I mean, you you've come to learn things. And that the opportunity to be able to learn from people at the LMB was, was just a phenomenal opportunity. And, and, and, and just like I quite wonderful thing. And I started to somewhat stumbled on this because a very good friend of mine, Bob Horvitz, who won the Nobel prize in medicine physiology with John Sulston and Sydney, Brenner in 2002, Bob and I have known each other since high school. And he was doing his postdoc with Sydney when I was thinking about where I wanted to go for a post-doc and it sounded very inviting, very intriguing to, to come there. So I, I, I view the, the time I spent in Bob Perlman's lab as a graduate student is not when I became certainly over-confident, but I gained some confidence that I could do some experiments. I could think about some things, but I think there was a real jump in getting to meet the people and interact with the people that we had it in the [Inaudible] group, and really all through the LMB. It was just a wonderful opportunity.

Peter O'Toole (00:15:32):
So the second question is, what type of supervisor are you?

Martin Chalfie (00:15:37):
Well, I am not a hands-on person but I'm certainly not a, um a person that completely lets people go. I I'm too interested in the experiments. I want to find out what people are doing. I like talking to people about the experiments that they're doing to me. And I've had this several times in my career. The, the wonderful indirection is when a, especially a graduate student, but also a post-doc comes and says, I was thinking about X. I had this idea. I tried it, I got these results and that's the start of the conversation. So they've gone off and they thought about something. They'd gotten excited about things they've started working on something, and then we'll be discussing it. Now the usual outcome of that is, oh, well, that's great. Keep going. That, what's the next thing you're going to do. But every once in a while, there may be a difference of opinion where maybe a control should have been done. Maybe there's an alternate hypothesis that should be entertained and we'll go into a discussion. And the discussion we'll both keep our points of view. We'll both somewhat be forceful about it, but in the end, we come up with a resolution either they've convinced me, or I've convinced them. And the very best cases of this are the people that say, yeah, you're right. I should think about that. I'm going to go do that by there's no ego involved. There's not a, oh, you thought of this. I didn't think of this. It's two people, rather than one person working on a problem and interacting and developing things. And I have to say, that's the part I really like, but I'm notorious about going around the lab and talking to people and saying, did you get that result yet? Or when did you find here? Or what are you working on now? And, and talking about it, I love talking about the ideas and trying to see how things go. It's so I'm, I'm somewhere in between that.

Peter O'Toole (00:18:08):
Okay. Obviously we need to touch on it. Your Nobel prize was for the work, which green fluorescent proteins, fluorescent proteins. When did you first start to work on that? And how long did it take to get anywhere with it? Because that happened overnight?

Martin Chalfie (00:18:29):
Well, yes. And so in 1989, I went to a seminar and the speaker Paul Brin it was an electric a neurobiologist was talking about some experiments he was doing on the species related to the jelly fish, a [Inaudible] Victoria, that is the source of GFP. I had never heard of GFP. I had known about the jellyfish and I had known about a Corin, which is a bioluminescent molecule that produces blue light, but I had never heard that there was this second protein GFP. And when it happened that this was at the time we were studying several genes in C elegans, we had started to clone, these genes. And one of the first questions we were addressing was what cell expresses a particular gene. And we, when we did this we used all the standard methods we made antibodies. We did in C2 hybridization. We use beta beta galactosidase which Malcolm Casadaban had introduced as a marker. And we all of these things worked. They were all fine. The problem was of course, that you had to prepare the samples. You had to fix them and permeabilized them to get the substrates in or the reagents in. And so you got a very static view, but I answered the question. We wanted to have the answer, which is, are the cells we're interested in the ones that expressed the gene, but this was the problem we were doing. The other thing is C elegans. By this time in 1989, I've been working on C elegans for 12 years. And I had this long list of the wonderful things about the worm that were why we worked on it. One of the main things was the animal is transparent. So in 1989, I want to know where genes expressed. I work on a transparent animal and I'm listening to a summer seminar where somebody is saying, there is a fluorescent protein, you shine blue light on it. You're going to get green light.

Martin Chalfie (00:21:02):
At that point, it stopped listening to seminar. I just fantasize about what was, what we could do. If this thing worked, we could look in living animals, we could do genetic screens. We'd look at protein localization. We look at gene expression, all sorts of things would come out. I just fantasize for the whole rest of the time, got in touch with Douglas Prasher. The next day, who I found was the person who was trying to isolate the cDNA, that encoded GFP. And we talked about, or we had a wonderful conversation. We decided to collaborate. And this was great. I loved having the idea to use this. He was thinking along the same way, the same line. So it was great, but he didn't have the full cDNA. And I waited for his call. Unfortunately, the call came when I was away on sabbatical the next year or later that year. And so Douglas thought I had dropped out of science because he couldn't get in touch with me. And I didn't know that he had called. So I thought he did not succeed in getting the cDNA. So nothing happened for three years. And then, but I still had this idea. I talked with various people, one person I really enjoyed talking to about this was Woody Hastings, who is just a wonderful expert in bioluminescence and fluorescence and everything at Harvard. I had actually taken a course from him when I was an undergraduate and an exceptionally nice person. And I would talk to him, where are the fluorescent molecules? Are there? Maybe we could use something else. And in October of 1992 we had the new graduate students come in or September or so, the new graduate students came in and they do rotations in lab.

Martin Chalfie (00:23:18):
And I had been talking with one [Inaudible], and Gia had just finished her master's degree in our chemical engineering department at Columbia and decided to get a PhD in biology, but her chemical engineering master's degree had been on fluorescence. So I trotted it out, this old idea for her and well, it's too bad Douglas. Hasn't gotten back in touch with me. It probably didn't work, but we should look for other things. And fortuitously university has just put on our computers, Medline, which was the precursor of pub med. And so I said, let's go look and see if there's any articles about fluorescent proteins. So we put that in search for fluorescent protein. And the first paper that comes up is a paper published earlier that year by Douglas Presher saying here's the full length cDNA for GFP. So he had gotten it, but he had lost track of me, the paper, had one remarkable thing that is usually not included in most papers. It had his new phone number. So I called him up. We renewed our collaboration and he sent us the cDNA clone that he had. And I gave it to Gia with the help of other people in the lab to help her do the cloning. She put it into e Coli. And then after she had transformed the e Coli, she looked at them in our microscope and we got a fluorescent microscope. It was old, it had too much glass in the light path. It was not very good machine. What

Peter O'Toole (00:25:20):
I was going to ask about microscopy was I better not say.

Martin Chalfie (00:25:24):
No, I don't think that's a good idea, but it was sort of old. And but she looked at it. She didn't know if her experiment worked or not, but she thought this is not a as good a microscope as I used to have in my old lab. And so she took the sample down to her old lab and she looked at it there and it was clear that it had worked. She had made green fluorescent e coli. This is one of the very rare times when the first time the experiment is done, it works. And that actually is what happens. So although it did take almost three years from the time I heard the seminar and talked to Douglas Presher about it. It actually was about one month or even less from the time he sent us the things because we were very fortunate and what her experiments said was it didn't need anything other than the GFP sequence. It didn't need a converting enzyme. You didn't need other situations. You just needed to express the polypeptide. And of course that was something that no one knew about. They knew that the chromophores for the molecule was made from the primary mineral acid sequence. They knew it was also a rearrangement of the peptide backbone making a five member green, and no one understood how that was made. And they thought, well, there must be some enzymatic change. There must be some converting enzyme. And so it will not work. So if the experiment had not worked, but the conclusion was going to be, well, there must be a converting enzyme, but the experiment work. It is its own converting enzyme.

Peter O'Toole (00:27:20):
And it is quite mindblowing. I, I think you could put all those obstacles in the way and say, well, it's going to need this. Bacteria is not going to have the right mechanisms, device, mechanics to convert it into fluorescent protein, let alone going into any other species, you know, and it would have been easy to talk yourself out of that experiment suck it and see was the quickest way to find out.

Martin Chalfie (00:27:45):
Yes. And there's also, it's not something you can write a grant for because the grant would say, we want to see if this works. And they would have said you don't have any preliminary evidence working. So it was just go try it. But I subsequently have found that three other groups, at least three other groups, tried to do the same thing to get GFP, to work as a marker. And they had contacted Douglas and gotten the cDNA from him. Now the cDNA that piece gave out was in a Lambda clone and it had the cDNA, but it also had flanking the coding region some extra jellyfish sequence. The other groups made their constructs wanting. I have often put it that we did our, they were careful and we were sloppy. And by that, I mean, if you want to make really good copies of DNA, you hire an expert. E-coli is an expert in making good copies of DNA. It's done so far. And, and so they put the sequence into a plasma at, or just through the Lambda clone, but that sequence brought, gave the frag. That was the coding sequence and the adjacent sequences to it for reasons that I can't really explain other than just, you know, fear, I didn't want to have anything extra. So I suggested to Gia that she used PCR to just amplify up the coding sequence and not have anything else from the Lambda clone and then use that with an appropriate promoter to drive the expression. And so the other people all had the flanking sequences and we did not. And there's something in those flanking sequences that make it not work. They did their experiment, it didn't work. And then you go back to the old hypothesis, which is there must be a converting enzyme that didn't work them. And now it's not as exciting, but we were just exceptionally fortunate because what were we were going to do? We were going to take all the DNA here. The problem with using just amplifying the DNA by polymerase chain reaction is that at the time the copying of the DNA was not always accurate. So you put in the stakes, but I didn't care because we were going to put this into millions upon millions of bacteria. So the bad stuff, okay. That wouldn't work. We would get enough of the good stuff. Some of the bacteria, if it worked on its own, we're going to be green. And that's in fact what happened. So that's what I mean by being sloppy, we didn't care if there was a lot of sequence or most, or maybe almost all as bad sequence, as long as there was some good sequence. And we were pretty sure there was going to be some, and that's in fact happened. But the people that added that extra part didn't get it to work. So yes, we were exceptionally lucky in many respects

Peter O'Toole (00:31:33):
And maybe slightly lucky your grad student knew where there was a better microscope because it failed because they wouldn't be non the wiser and you'd have had it. It would have been there and you wouldn't have seen it. Wow. So

Martin Chalfie (00:31:48):
Yeah, Gia gives a very smart person.

Peter O'Toole (00:31:52):
What would you say has been the most exciting period of your career?

Martin Chalfie (00:31:59):
You know, I, I feel that everything is exciting period. In my career, people look at the Nobel and they think, oh, that must be the most exciting thing. And it was exciting to think about GFP to actually have the experiment work, but we've worked on a number of things. And I have to say, I get excited about all of those. I get excited about having ideas and having the rare time when those ideas actually work. It's, it's really terrific. So I did, we're always in a situation where things are exciting. GFP clearly was the most impactful thing that we worked on, but we worked on a number of things. And when things sort of give you new insights or new ideas I find that very exciting. So I, I don't think I, I pick anyone it's like saying, which one of your children do you like the best, but

Peter O'Toole (00:33:00):
That was my next question.

Martin Chalfie (00:33:02):
Well, I only have one child and I do like her the best. So that's wonderful

Peter O'Toole (00:33:10):
Actually thinking of child I was going to go somewhere. So I think because you've got children, obviously you're married and I believe your wife allowed you to cite the, an unpublished work on that on, on the biggest, by citing

Martin Chalfie (00:33:26):
What we did. So after Gia had shown that GFP could work on its own expressed in bacteria, the technician in the lab, Yan tu put GFP into C elegans. And we were able to label the cells that we've been working on. Most of the time I've had a lab, which are the cells that sense touch and see elegance. And we were able to show it worked in C elegans. And at that point we knew it would work. It wasn't specific to one organism or another. We had Ecoli, we had worms, we already knew it worked in jellyfish. And we started to write up the paper and as you know, writing up a paper takes some time and everything. I started telling people and people started asking, could they get infact? Although the paper eventually came out in February of 1994, we have a newsletter in the seal against field called the Worm Breeder's Gazette, or we used to, and in it, the October, 1993 issue of that, I told the world about GFP and said, if you want, it write me a letter we'll work through this. And so people were all people, so people knew about it, and we were already distributing Aliquots. Now, what we had shown was that GFP could be driven by a promoter of a gene. So we could see where a gene was expressed, but there were many other experiments to do. And other people started doing them. And one of the most important experiments was done by my wife, Tulle Hazelrigg, working in fruit flies in which she wasn't as interested in where, what cell expresses a given gene, but rather the gene makes a protein. Where does that protein go? And so she made what's called a fusion in which the protein she was interested in was linked to GFP. So wherever that protein went, she could follow it. And her particular protein was a really exciting one because it was made by what was called the nurse cells in the ovary of fruit flies, and then brought into the developing oocyte. So she could see GFP protein made in one part of the developing germ cells, and then shunted over to the developing lower oocyte. She can actually watch it and move. And this was a very exciting thing. She also did a very important experiment. How do you know that what you're looking at is actually any thing related to reality? Well, in her case, she knew that if she got rid of her protein, then the embryos didn't develop, they just died. If she put the wild type, the normal protein into the animal, then of course they lived, if she put the wild type protein hooked up with GFP they lived. So that says that GFP attached to the protein still allow the protein to do its job. And so very important control. Well, when we finally finished writing the paper and it was accepted, we wanted to put into it. Uh the news that various people had gotten back to us about that said GFP worked in their system. So it wasn't just a couple of places. It was quite a few places. And so I wrote to people and I said, I'd like to cite your unpublished work. And they said, well, look, you gave us this thing before you publish it. Of course you can do that. Except my wife who has a wonderful sense of humor wrote this letter, saying that I had to, in order to cite their work, I had to make coffee every Saturday for two months, I had to take out the, I had to prepare a special French dinner and I had to take out the garbage nightly for a month. And this was very funny and I've shown this several times in talks, but in fact it was not the letter that was sent to science magazine, giving her permission for us to cite her work. But it, it, it, it was very amusing and she knew when to put the pressure on it's like,

Peter O'Toole (00:38:36):
Did you live up to it? Did you?

Martin Chalfie (00:38:40):
So I have taken out the garbage a number of times I've made coffee quite a lot of times the French dinner. I'm not so sure, but I have cooked other meals and I'm going to declare that those were French dinners, even though they may have pasta in them or something else, but I'm sure I cooked some French thing at some time or another. She will debate this profusely. I would say that I, I, I, I would declare that I have lived up to the agreement in any case, we cited her work and her work actually came out about four months later publishing and was really the second paper that utilize GFP. And, but this time talking about it as a protein fusion

Peter O'Toole (00:39:36):
On the making food who cooks at home,

Martin Chalfie (00:39:40):
We both do. She cooks a little bit more because she's a better cook, but I, I tend to cook a fair amount and we try to share things.

Peter O'Toole (00:39:54):
And what's your what's your signature dish? What's your favorite meal that you cook?

Martin Chalfie (00:40:03):
Recently there's been a, sort of a single dish gnocchi with Brussels sprouts that we've liked a lot, cook that every once in a while, there'll be, I'm sort of addicted to the New York times cooking information. So every once in awhile, when there's something there, I'll try to cook something there, whether it's a candy or cookies or things like that, these are dangerous things to cook. But I don't have a particular, I have a particular favorite dish but it's, it's a spaghetti casserole that my mother used to make. And I it, it was all, it was sort of the comfort food at home. It remains the comfort food. We don't make it that often, but it is, it it's, it's, it's one of those nice things to make.

Peter O'Toole (00:41:01):
Oh, w which is brilliant, I'm going to go back. You said with the New York times, you look at the cookies, the candies, and you get, you're doing gnocchi with brussel sprouts.

Martin Chalfie (00:41:12):
Th that's because cookies and candies are not that frequent as they should not be,

Peter O'Toole (00:41:21):
Oh, sorry. Gnocchi and brussel sprouts doesn't sound like that should be very often either.

Martin Chalfie (00:41:26):
Well, you know, during the pandemic, it was a good thing. As, as, as other types of things there, there was actually recently a wonderful recipe for an Indian style nachos, which we made, which we quite liked. And so there were all sorts of exciting things to, to just try.

Peter O'Toole (00:41:49):
Okay. So you go, if you eat out, what would be your favorite food style if you were to go out and eat?

Martin Chalfie (00:41:58):
That's very interesting. We don't eat a lot of meat at home, so basically it's not so much a style, but I I really like lamb chops, but usually when I go out, I often get a lamb chop. I mint sauce you know, in United States, it's mint jelly, which is sweet as opposed to the English or the British sort of mint sauce, which is vinegary. I, I tend not to do either. But I I, I, you know, I'm quite open to all sorts of things. I, I really liked sushi. I really like Korean food. I like just a whole variety of things. One of the things I don't get enough of that I enjoy doing is Ethiopian food, very emjoyable.

Peter O'Toole (00:43:07):
That's different. I've not had that answer before.

Martin Chalfie (00:43:12):
You know, it's quite, it's quite good. Your, they, they have a wonderful sort of spongy bread. Called JIRA that you've basically used to, to eat various types of stews. And I kind of very, very good.

Peter O'Toole (00:43:28):
Now I know what to ask. One of my staff to being back when they can, they, we've got a consortium, which in pleads Ethiopia, and they go over there to do some training. I know what to ask. It's being back now. So red wine, red wine, white wine beer, go on, what's your alcoholic choice,

Martin Chalfie (00:43:48):
Actually whiskey. But I would say of the three that you you've said probably red wine, red wine or beer,

Peter O'Toole (00:44:03):
And the Whiskey, Scotch, Bourbon.

Martin Chalfie (00:44:07):
Actually both when I was a graduate student with Bob Groman, every time we wrote a paper and every time the paper was accepted I go into his office and he take out this bottle of Scotch Whiskey from his desk. And we get out the five or 10ml beakers, the really tiny ones. And we'd have a little beaker to sort of toast that the that this has work. And when so this was our tradition a which I quite liked. I haven't kept up that tradition, which is unfortunate.

Peter O'Toole (00:44:59):
I'm glad you did it only when you publish a, not for every citation.

Martin Chalfie (00:45:03):
Well, that would be good too. But this was, this was what the tradition was. In any case, when I came to England for my post-doc, I went to off license or whatever it's called, and I was talking to the proprietor and he said, oh, this, this is a very good Scotch whiskey. You should, you should you should try this. And I liked that one. I should also tell you that when I first came to England, before I did my went off and started my post-doc, I went on a two month trip spending most of my time in Scotland. And at one point I found a small, a sampler of certain airplane size bottles of different single malts. And I had sent them to Bob Groman sort of remembering this thing. And then about two years later, Bob and his family came to London and I went down to see him and we went for a walk and I said, Bob, I know how much you like Scotch Whiskey. I have found the very best one. And he said, no, don't, you're not going to change what I like. There's one that I like. It was one of the samples that you sent me and that's become my favorite. I am absolutely. There's nothing you can say that had changed my mind. And we argued about this for about five or 10 minutes until we discovered we were talking about the same Whiskey Highland park.

Martin Chalfie (00:46:49):
Really? Yes, we both liked it. Park has changed over the years, but at the time there was only one Highland park in 1980, or at least it seemed to me there was only one and we both quite liked it.

Peter O'Toole (00:47:03):
I'm going to have to get a bottle now.

Martin Chalfie (00:47:08):
But I also like bourbon. I don't drink a lot of these, but every once in a while it nice to have

Peter O'Toole (00:47:18):
I asked earlier about the most exciting time. What about the most challenging or difficult time you've had in your career?

Martin Chalfie (00:47:26):
The most challenging time I've already talked about, which when I was undergraduate and I really, I really should have had somebody take me aside and say, stop being an idiot, just relax ask people questions. And this is how you should probably approach things. I think I was too naive. I think I was I, and I talked myself out of things. I think that was the worst aspect about it. I had this idea that real scientists, whoever they may be were somehow destined to be real scientists. There was something innate about it. And there was the natural that, that seemed to be able to do it. And if you weren't that person, then you weren't very good. And I see this in undergraduates a lot. I was talking some years ago to the chair of the chemistry department and he was saying how upset he and the other faculty members in the chemistry department work because undergraduate start off the first course that they usually take is general chemistry. And he said, there were these wonderful students that were there and they got a B on the first exam. And they said, there I've proved from, to myself. I'm not good enough to do this because they had said, I have to be perfect in order to get this. And I certainly sort of felt something like that when I was an undergraduate and it really is. I'm not perfect and I'm never going to get there. So I shouldn't be doing this. And I, I, it it's really unfortunate. So I would say that that was probably the most challenging part of, of, of, of this is sort of talking myself out of something that I really enjoyed.

Peter O'Toole (00:49:34):
Only take you back to when you were about the age of 12, what did you want, what job did you want to do when you were a young child?

Martin Chalfie (00:49:41):
I had no idea what I wanted to do. I certainly liked math. I liked the sciences. I, you know, I, I, I enjoy finding out about the sciences. So I, I probably thought I was going to do science of some sorts. Science or math, but I, I had no real idea about what I wanted to be when I grew up. I knew I wanted to be grown up, but I didn't know what to be.

Peter O'Toole (00:50:15):
When you, when you left academia and I know you ended up selling dresses, I think in your parents' shop, where did you see your career going there? What did you think you might like to do at that point?

Martin Chalfie (00:50:28):
So, after I decided that I wasn't going to be a scientist, I had a wonderful final year in college where I took courses on all sorts of subjects that were just interesting to me. And then I even took some courses afterwards in sociology. And then I decided I'm not going to do this. And I did a whole series of one month jobs, and I didn't really have a clue as to what I wanted to do or where I was going to go. I knew I needed to get jobs. I had to pay for things like food rent and, and things like that. But I, I didn't have particularly any goal. And these the, the dress selling job was a wonderful job by from an unfortunate situation. My father got ill and the family business, which had been set up by my mother's mother, my grandmother was a remarkable person. Um and it was a family business at the time, my grandmother, but mainly my mother ran the business, the office, the dress manufacturing, part of it, and an uncle. And my father were the salespeople that would take the line of dresses all around the country. And my father is part of the country was from Chicago to the east coast. And he got ill and he couldn't take the line around. And I was, I finished college, I wasn't doing anything. I just, the done one of the one month jobs I had been working on. And so I was the one that was going to do the, so I took the line around all these shops and I learned an enormous amount of about my father that I just I'm so grateful that I did this because I hadn't really understood what he was doing. He had a very interesting way of selling, and that was, there would be one store in the town that he would sell to. The tone was fairly small. And that was the one store there that was fine. But New York city only had one store that he sold to. And Boston only had one store that he sold to. And these are the type of dresses were for professional women and wives of executives. And it was just early, early it was 1970. And so they were fairly expensive. So this we're special, we're called specialty shops. And my father not only had just one place that he was out, but he never tried to oversell anything so that when P when he came by, people knew exactly what they were going to get. They had had years and years, some cases, decades of in association with him and what knew what it was. And so when I came, there was no selling. I had no how to sell these things. I would simply walk in, open up the collection and the owner and the buyers, and the salespeople would take a look at them. And they say, you know, Mrs. Brown would like this one in green and Mrs. Smith, but like that one in red and Mrs Schwartz she'd like that one in blue. And they had all their customers in mind, they'd order just enough to sell the people they knew they were going to sell items would come into their store. And in due course, they display them. And then other people would say, oh, I'd like that. What colors does that come in? And then there'd be another round of ordering. And everybody was happy. And it was the easiest job for me to do because I just went from one place to another and just opened it up and then sat there while they decided what they wanted, because they, my father had built up this amazing trust with them. And, and that was really wonderful to see, but there was actually one new person my father wanted me to see. And I went to see, my, my parents had called this guy up two or three times. Our son is coming. He's going to show you stuff. This is not what he usually does and everything. And the man later told my father that when I came in, it was clear that I'd had, he, he knew, I knew nothing about the dress business. And so, and he said, I felt sorry for him. So I bought three items and it was the best thing I ever did because people would see them in my showroom and they kept ordering them and ordering and ordering. So he felt he was being kind to me for doing this. And he became a good friend of my father's and, and a good customer. But it was very interesting seeing this no pressure sales approach and trying to build up a rapport. That was my father's way of interacting with people. And it was just quite wonderful to see that firsthand.

Peter O'Toole (00:56:14):
I think he's fascinating to see how parents work and how they operate is different to how they have at home and different management styles.

Martin Chalfie (00:56:21):
I did not want to be in the dress manufacturing business that I had no idea what I was doing, but that was not what I was going to be well for one month, I was very happy to do this. I really didn't know what I was going to do until I was teacher. As I said, I was teaching school. And then got this job working in a lab. And the thing I didn't talk about that experience, but it was quite wonderful. I had mentioned Woody Hastings before, as a, as a person that I had really respected. I had taken a course in my junior year from Woody Hastings, and I had to write a paper for this course. And in writing that I wrote this paper some work that had been done with a particular type of ion transport. I later found the paper, I guess I had kept it. It did not get a very good grade on the paper, but I remembered what it was about in any case. I hear about this job working for a man named Jose, [Inaudible] at Yale? I go to see Jose and he starts telling me about his work and he's working on an absolutely fascinating problem. One that I had never realized was a biological problem. And I now use this every once in a while in my talks. And I say to people, you know, the first place I had a published paper, I was working on the transparent part of the body. How many of you in the audience know what the transparent part of the body is? If you know don't say it, but just raise your hand. And I see people looking at their wrists and you know, what is the transparent part of the body? And about five, 10% of the people raise their hand. And I say, well, I'll give you a hint. It's right in front of your eyes. And eventually people start to realize that it's the cornea or the lens, and you can get more complicated than that, but the cornea and that's what he was working on. He was working on the cornea and how it maintained its transparency. And he was telling me that in frog, where they use the cornea, that this was a chloride transport, that chloride was shunted out of the cornea because there had to be a certain amount of hydration, unfortunate people that scratch their corneas, they become swollen and they become sort of opaque. And which is a problem. But if this pump is working, chloride gets shoved down, potassium file follows the chloride, ions, water follows that. And so there's a certain amount of height dehydration, and this is tested. It was an easy way of testing, how fast the transport is going by a machine made by a Swedish or apparatus made by a Swedish scientist. It's called boosting chamber. Basically you put the membrane that steaks the cornea between two reservoirs. And you look at it, you measure the amount of current because the chloride is negative charges moving across it. And you figure out how much current do I need to put in the opposite direction to bring it to zero. It's called a short circuit current because you bring it up to zero. And so the more the transport, the more current you need in the other direction, and you could measure this. And so he's telling me about this. This is what they do in the lab. And I remember the paper I had written as an undergraduate on transport. Now I got a lot of the details wrong because they were working on frogs as he was, they were working on toads.

Martin Chalfie (01:00:25):
They weren't looking at chloride transport like he was, they were looking at sodium transport. And it was not the cornea. It was skin so completely different system, but they use the same chamber that's well remembered. And I remembered their conclusion. They had found that their transport could be turned on by ways of increasing cyclic amp. And so I asked Jose in my interview, does cyclic amp have anything to do with this? And he looked really surprised and said, I don't know, but you're the second person in two days to ask me that question. And so I said, okay, great. I think it's because I asked him a question in the interview that he'd decided to hire me. So I consider that the first miracle and I got hired in the lab and he gives me a project that even I thought then was a little bit boring, but I'm going to work in the lab. And then a couple of days after I start working in the lab, he comes in and announces to everyone. Goodbye. I'm spending the whole summer in France, working on fish, I'll see you in September and he leaves. So now I'm alone. Well, not really. I'm just a postdoc in the lab who knows how to set up the apparatus can help me on it. I find the other person who had asked the question about cyclic amp, who was a post-doc in a different lab. And I go to him and I say, if you were going to test cyclic amp as a mediator, huh? What would you do when you said, well, I would throw adrenaline on the system and see what happens. I thought, okay, I can do that. I set up the experiment. I put adrenaline on the thing, went off scale. I spent the whole rest of the summer doing my experiments, not doing the experiments that I had been told to do, hired to do. And I went to the library and I looked up literature and everything. And so when Jose came back in September, he said, so tell me what, because it's 1970, there's no email. There's no faxes. There's he didn't even want me to send them regular mail letters. So he didn't know what I was doing at all.

Peter O'Toole (01:03:08):
How worried were you, you got off piste.

Martin Chalfie (01:03:11):
Yeah. So

Peter O'Toole (01:03:13):
What were you worried about it when you're going to tell him that?

Martin Chalfie (01:03:17):
Oh, no, because I had results. I wasn't worried at all. I would say it was a little naive, but maybe stupid, but I, but he came back and I said, he said, well, what happens with potassium? And I said, I didn't do those experiments. He looked a little surprised. I said, but I did these experiments. I've gotten this information from the library and here's, here's what we had. And he was very happy with that. And that did become my first publication how I had the nerve to do all of that. I'm not entirely sure. Somebody once told me this wonderful, horrible line that somehow derives from WH Auden who said something somewhat similar, which is everyone likes the smell of their own farts. And you like your own ideas, whatever, how badly your ideas smell you liked them. And so I think this idea of being able to pursue this to go and just try to do the experiments and having the experiment work, that was really exciting. That was a real surprise. I actually got something to work and that's what convinced me to become a graduate student. They continue on in science that, you know, sometimes you can get ideas and the ideas will work. Even if the ideas coming from the completely wrong direction, sometimes things work out. It's very exciting when they do

Peter O'Toole (01:04:52):
Marty. We are just at the hour mark and I have to ask some quick questions because I'll try to

Martin Chalfie (01:04:59):
Give quick what

Peter O'Toole (01:05:00):
They are. If you could do any job today, what would it be?

Martin Chalfie (01:05:08):
You know, I quite liked the job I have. Aye, aye, aye, aye. I really do like working in a lab. I really like working with, and I have to say, and I have to say that the Nobel has had one really amazing consequence. I don't know why, but people ask me to be part of other enterprises. And one that I have really enjoyed has been I'm the chair of the committee on human rights of the national academy of science, engineering, and medicine in the US and being able to see the people that are so devoted to other people and their rights and concerns and everything has been really wonderful to be part of that. So I think, you know, when people get a Nobel sometimes think to yourself, now I have to do something I have to, to, to make this worthwhile. And this has been, I mean, an incredible opportunity to get to meet some amazing people and to lend a hand helping other people. So I, I, I sort of like what's, what's happened to my life. I would love to be a professional guitarist, but I'm never going to get to that place. That's ok

Peter O'Toole (01:06:39):
Early bird or night town, early bird or night owl.

Martin Chalfie (01:06:44):
Oh, definitely. Early bird way too early. And then I fall asleep during the day.

Peter O'Toole (01:06:49):
Okay. what's your favorite TV show?

Martin Chalfie (01:07:00):
One of the TV shows I really liked was a three season series show from Canada called Slings and Arrows of no It's about a Canadian Shakespeare or theater company that puts on a different major Shakespearian play for each year and each one of the seasons. And it's very, very, very good.

Peter O'Toole (01:07:27):
Okay. Favorite movie

Martin Chalfie (01:07:31):
Favourite movie for many years or nights still say it is That Man from Rio with Jean-Pal Bemondo also I'm blanking on the name of, I won't remember the other movies, but That Man from Rio. It was definitely one of my all time. Favorite

Peter O'Toole (01:08:04):
Favourite Book.

Martin Chalfie (01:08:05):
Favorite book is Dear Committee Member by Julie Schumacher, which is one of the funniest books I've ever read. It. It's a, it's, it's something that all academics should read and should enjoy. It is an epistolary novel, but the letters that are the basis of the novel are all letters of recommendation of expanding one year by a English professor and my wife and I give this book as presents to almost anybody. And when we do people usually write back and say, I want to write letters like this guy is writing letters. It is a wonderful, wonderful Dear Committee Member by Julie Schumacher

Peter O'Toole (01:08:58):
Final quickfire question. What's your favorite color?

Martin Chalfie (01:09:03):
Favorite color? You know, you you'd expect me to say green, but it's actually blue.

Peter O'Toole (01:09:09):
I origami behind you. There

Martin Chalfie (01:09:14):
Yes.

Peter O'Toole (01:09:15):
And it's blue and white.

Martin Chalfie (01:09:18):
Yes. Yes. For a while there I, I was, I, there were a couple of books of making sort of geometric figures with origami and now my hand doesn't work quite as well as it should. So that's something from the past.

Peter O'Toole (01:09:35):
Okay. So finally I know we're over time. Do you have any top tips for anyone? I think you've actually given lots of top tips, which I get. I just try it be adventurous and try it. I guess

Martin Chalfie (01:09:49):
Not talking oneself, out of things I think is the most thing is the best. I think the other thing is to ask questions. We, we, it is always surprising to me how much we don't ask questions about the world around us. That example from the cornea is one of these. We've all been looking through our eyes, hopefully. And we, but, and, but asking the question, even though maybe 10% of the people will be able to ask the question, what is the transparent part of the body I've actually never met? Anyone else that has said, you know, I've often wonder what makes the cornea transparent. It's just one of those questions that's been out there, but we don't ask questions about it. I think asking questions, asking questions about our assumptions. I have a former colleague wonderful scientist. Rouman Pu neurobiologists. And I remember one day we were talking and I said, Rumi, you've had, or somebody said, no, you're moving. You've had so many wonderful ideas at the basis of really great discoveries. Where do you get your ideas? And he said, well, and he said, his secret was that he took a textbook in his case the second edition of molecular biology of the cell. And he read, he says, I read through the textbook and I simply asked myself the question, what's the evidence behind this statement. And I try to find out what the evidence is and if the evidence isn't strong, I do the experiment and he was making great discoveries because we do base a lot of our ideas on previous experiments that are extensions of what we think is happening in world. We change what we know and so questioning ourselves, questioning our assumptions and looking at things in a number of the other thing is there's this wonderful line by Enrico Fermi, that goes something to the effect that if you do an experiment and it confirms your hypothesis, then you've made a measurement. But if it doesn't confirm your hypothesis, then you've made a discovery. And so the discoveries are the unexpected thing. That means you have to do a lot of experiments and be surprised at the unexpected results and think about them. They do come, they may be important. They may not be important, but it's those surprises that lead into the new directions that, that people have. So being aware that things are not going to work exactly the way you think they are, and maybe that's telling you something important. Okay?

Peter O'Toole (01:12:53):
Why are you never skeptical? And when the result comes so quickly, I'm always skeptical when the result looks to.

Martin Chalfie (01:12:59):
So when I was a graduate student, I worked with John Sulston, who is one of the absolute great people and great experimental. And one day I came to him all excited about a result that I had told them the result. And it was this wonderful thing up. We had been working on at work and it's great. I was super enthusiastic about it. And then I repeated it the next day. And of course it didn't work. I went to John, all apologetic, and I said, John, I shouldn't have said anything. I should have not been as enthusiastic. And he just looked at me and he said, you know, I actually never believe a thing you say, unless I've heard it three times. And that was his rule for everything that if he heard of a result three times, then you believe it. But now I think it may come from the hunting of the snark where I think it's a [Inaudible], I've told you this now three times, it must be true, but I think it's a really good thing. I think people should be enthusiastic about what they're doing. Get really excited about the resolve and then repeat it. And if you can say it three times, if you find the result three times, that's terrific. So the enthusiasm has to stay there.

Peter O'Toole (01:14:21):
I guess on that note, we'll have to do this podcast three times over, but we are active time. Marty, thank you very much for joining me today and thank you everyone for listening or watching. And please don't forget to subscribe to The Microscopists on whatever media you're listening to it. Marty. Thank you very much.

Martin Chalfie (01:14:39):
Thank you. Peter has been a real pleasure.

Intro/Outro (01:14:44):
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/themicroscopists