Stuart Lindsay

David Zierler:

OK. This is David Zierler, oral historian for the American Institute of Physics. It is June 17th, 2020. It is my great pleasure to be here with Professor Stuart Lindsay. Stuart, thank you so much for being with me today.

Stuart Lindsay:

David, you're welcome. It's a pleasure.

Zierler:

OK. So to start, please tell me your title and institutional affiliation.

Lindsay:

So, I am a professor of physics and chemistry. I hold the position of a university professor and a regent’s professor. My affiliation is the Biodesign Institute at Arizona State University.

Zierler:

OK. And now let's take it back all the way to the beginning. Tell me about your parents, where are they from?

Zierler:

Well, where is she from? I grew up in a single parent family. My mother was a war bride from Germany originally. I grew up in the U.K.

Zierler:

So you don't know anything about your father?

Lindsay:

Not really. I know of his family, but saw very little of him as a small child.

Zierler:

But you did have contact?

Lindsay:

When I was tiny. Yes, sort of at the point of not having any memory.

Zierler:

And did you ever try to establish contact later on?

Lindsay:

Yes. And it wasn't particularly pleasant.

Zierler:

And where was your mom from?

Lindsay:

She was from Berlin. And so moved to Britain right after the war, and obviously had very tragic memories of the war. When she, in retirement, came to live with us in the States, she wouldn't talk about her wartime experiences. And when her former property outside Berlin became available with a change of government and the fall of the Wall, she wasn't interested in reclaiming it or having anything to do with it. In fact, we grew up thinking we were more British than the British because my mother was so fiercely patriotically British.

Zierler:

What was her family background? Where did she come from?

Lindsay:

So, I think a business family, fairly well-to-do Eastern European. We actually found the family summer home, after she died, in eastern Germany and they were obviously well off. But then, of course, the war changed everything. She was married during the war, but to a Russian, White Russian, which wasn't a particularly good idea at the fall of Berlin. And she lost that husband and a baby to the incoming Russians.

Zierler:

So obviously, she was horrified by what the Nazis had done.

Lindsay:

Yes, she had Jewish friends and relatives. And as I say, it was just something that she never really talked about, and my brother and I were convinced she was as British as could be. And I think it was only after she died, listening to recordings of her speak, that we realized she had a German accent.

Zierler:

[Laughs] So she didn't speak German to you when you were a kid?

Lindsay:

No, not at all. And in fact, we grew up so anti-German that when I took a sabbatical in Stuttgart, I did my best to learn German to make up for that deficit because, of course, I have a lot of wonderful German friends. But it was a it was certainly a scar, growing up as a as a kid.

Zierler:

Was she open about her identity with you? Did you know, growing up that she was German or he tried to whitewash everything?

Lindsay:

No, it wasn't that she tried to hide it. It was just that she was so fiercely patriotically British that it never occurred to myself, or my brother, that she was German, which is ridiculous. We do remember schoolmates of ours referring to her as "that Continental lady" but we had no idea why.

Zierler:

And what was her profession? How did she support the family?

Lindsay:

She trained as, in Britain, it's a chiropodist and here it's podiatrist, I guess. So she taught herself and I mean, she took, you know, night classes and that kind of thing. She was a very loving lady, very eccentric. We had a completely undisciplined childhood. But she was a wonderful woman. And as I think I told you, she came to live with us for the last 10 years of our life in the United States.

Zierler:

Did she ever remarry?

Lindsay:

No. No.

Zierler:

Tell me a little bit about the neighborhood where you grew up.

Lindsay:

I grew up in many places. London to begin with. But then a little seaside town in the UK, an Edwardian sort of place, that is pretty decayed now. But it was actually lovely. I mean, being by the seaside, meaning that you were completely by yourself in the winter, right? No seaside visitors. It was an enchanting little place. We had no money, but I was very happy in that environment.

Zierler:

What kind of schools did you go to?

Lindsay:

Well, a whole series of them, because the family moved around a little bit. But state schools. As you know, in Britain, public school means something different. So these were state schools. And eventually, I don't suppose any American is going to believe this, but eventually it turned out that the County Council would pay for children from broken homes to go to boarding school, if you can believe that.

So I went to quite a good boarding school where I was incapable of taking advantage of what was on offer because of my rebellious attitude and total lack of self-discipline. And I did, in fact, eventually get expelled. However, I got infected with physics there, so there was a good outcome.

Zierler:

So you qualified as coming from a broken home, even though you had a good mom who supported you?

Lindsay:

Yes. I mean, that's the way it was, you know, in Britain. Britain in the 60s had some appalling aspects, but very strong social programs.

Zierler:

So at what age was it when you fell in love with physics?

Lindsay:

I'm trying to think. Probably around 15. I mean, I've always loved science. So, one of the side effects of not having a conventional home was enjoying being by myself. So as a little kid, I used to collect fossils, used to, you know, build up my own chemistry sets and make things that you could make in those days that went bang, that you can't make now. And I was a radio ham, so I had lots of interests, but no academic interest in science.

The key turning point came when our physics teacher at that school that I didn't realize was a good school decided to give an extemporaneous lecture on the Bohr's Theory of the atom. And I just remember it vividly because I would have told you I hated mathematics, the hard work. Who wants to do those boring problems? But I just remember the electric shock going down my back, a frisson, when Tom Leimdorfer, the physics teacher, arrived at this formula with e's and h's and m's and c's and put the numbers in and out came the Rydberg. I remember thinking this is the most incredible thing I've ever seen in my life. And that was, flick, the switch went on, so after that I started reading physics books and so on.

Zierler:

Was it that it was so elegant that it worked so perfectly?

Lindsay:

Yes. And it was that you didn't just have a theory or an argument here, you had something into which you could put numbers and test it with precision. That to me, was a shocking, almost religious revelation. I didn't realize human beings could do this.

Zierler:

You could take all subjectivity out and it's just truth, right there.

Lindsay:

Exactly. Of course the Bohr model is absurd, right. You took this absurd model, and you took constants of nature and came to this conclusion. I just remember thinking that was wonderful. So in the time I had available, with no formal schooling as a result of having been expelled, I spent in the library reading physics books.

Zierler:

That's how it happened.

Lindsay:

That's how it happened, yes.

Zierler:

What kind of prospects under those circumstances did you have for an undergraduate education?

Lindsay:

Oh, that was interesting. I didn't do too badly at school exams. I didn't do wonderfully either. But I also, as a result of one of my hobbies, had published quite a bit. As I said, I was a radio ham. And in those days, there were magazines like Practical Wireless and Practical Television and Wireless World and Shortwave Magazine. And I used to make money for my hobby by writing for them. So I wrote a lot of technical articles, you know, projects I'd worked on and so on. And I guess that meant that I got ridiculously facile offers from good schools, so I ended up at the University of Manchester.

Zierler:

So you did not graduate formally from high school with like an equivalency exam?

Lindsay:

Yes, actually, yes, that's right. I went and took, in those days, there wasn't a graduation, per se. You took a A-level exams in the UK. And so I finished up my A-levels exams actually on a different syllabus from the one that I started at the school I didn't do too well at.

Zierler:

So when you were thinking about schools, you were thinking specifically about physics programs?

Lindsay:

Yes. Yes, absolutely. For no strong career goal. Just that I absolutely loved physics.

Zierler:

Well, that's how it works. Of course, when you don't think about a career and you have the love, the career comes.

Lindsay:

Yes. Yes.

Zierler:

Where is Manchester in the rankings in terms of physics programs?

Lindsay:

It's really a great school. It's up at the top. I would say Cambridge is better, but I mean, you know, it's a toss-up. But Manchester was the home of Rutherford, and in fact, Rutherford established the curriculum there. So it suited me to a T because, despite being a brilliant theorist, he couldn't stand theorists. And so you could get an undergraduate degree by spending all your time in the lab, which suited me perfectly. So it was an excellent program, and they gave me a ridiculously trivial offer in terms of grades for a place - that was shocking actually, no one believes it now. And it was just a great, fantastic program. The only weakness I remember was special relativity when the lecturer came in and scribbled something down on the board, and, you know, we were spotty freshmen. And myself, particularly lacking a lot of mathematics. And he heard the deadly silence of the class and turned around and said, you've all seen the Lorentz transforms in tensor notation before, haven't you? And it went downhill from there. [Laughs] But other than that class, I just I just thought it was the most fantastic experience. Great school. Lots of hands on lab experience. Lots of rubbing shoulders with some really great researchers.

Zierler:

Now, in the British system, you're fully committed to your major from day one.

Lindsay:

Exactly. Yes.

Zierler:

And so between that and the heavy focus on being an experimentalist, you really had a head up, in terms of, I mean in the American system, people go to graduate school and they're still not sure if they're going to commit a theory or experimentation.

Lindsay:

Yes, I guess that's true. And the British system has its weakness. I mean, when I started teaching in the US, my first assignment was the theoretical mechanics. I remember not knowing half the words of the syllabus simply because I hadn't had that experience of an American graduate school. But on the other hand, being able to run a research project and, you know, get yourself up to speed as an expert in relevant areas, as you thought fit, was a great experience. So, I really enjoyed and appreciated my education there.

Zierler:

Now, in terms of working in a lab as an undergraduate, did that mean that you had to develop a relationship with the professor and then get problems from him?

Lindsay:

It was a little bit more prescriptive than that, although I mean, formally they were sort of lab classes. But the folks who taught them interacted with the groups in the labs because you had assignments that might involve, for example, a theorist. So for example, my joint theory and experimental project had as my theory advisor, Sam Edwards, a.k.a. Sir Sam Edwards, who's very famous in polymer physics and an outrageously abstract theorist. So you interacted with a wide variety of people and although the labs were perhaps nominally defined, you were completely free to take them where you wanted to, which suited me fine.

Zierler:

So very few classes in theory?

Lindsay:

Very few classes in theory that were obligatory. And I have to say that although I loved physics, it wasn't my intended career goal and I was actually pretty badly at class and exam work until the very end when I decided I'd better do something.

And so all of my theoretical background came from going through texts and doing problems in the weeks before final exams. In Britain, everything hinges on final exams. So, you know, that was where I bought myself up to speed in the general curriculum.

Zierler:

Was there a senior thesis?

Lindsay:

No. Well, that isn't true. There was a long experimental project in which took an entire semester, which in my case was doing phonon-assisted tunneling spectroscopy through inelastic spectra using a tunnel diode in liquid helium, which was a fascinating project. Lots of solid-state physics in it. And what was particularly pleasing was, one of the articles on the subject from Bell Labs contained some intriguing things that, I think they called them Wigner oscillations, and I showed that they definitely weren't. I showed them to be an experimental artifact. So I suppose I could have published a paper on that, but never did.

Zierler:

But now in the States, there's varying opinions about stay where you are for a graduate program or going somewhere else. You know, like the Harvard model is why would you go anywhere else? You're already at Harvard. You know, I suppose the drinking different wine. How did that work at Manchester?

Lindsay:

So, you know, I didn't really think about it. I had lots of commitments in the area. I was actually very active in politics, and that's another side story right there. But I had reasons for staying in the area. And I ended up with actually an excellent degree, which shocked me, near the top of the class which was like 180 students in that class. So that's not where I expected to be for sure. And so I was pretty much top of the list for getting a research assistantship. So it was sort of a no brainer to do research there. And my advisor sort of jumped the queue ahead of other advisers by offering me a pretty decent, for the UK at the time, summer salary to go work in his lab. So I thought, why the heck not? And so I ended up in polymer physics, which is actually quite close to biophysics, so it was it was a good move.

Zierler:

Now, I was going to ask you about the political aspect, because, of course, your undergraduate education coincides perfectly with the late 60s and the early 70s. My question is, did Manchester see a lot of the counterculture? Was that there on campus?

Lindsay:

Oh, absolutely. But that was actually the reason why I was part of the counter-counterculture. I think my colleagues nowadays think that I'm a neo communist. But in those days, my wife and I were very active Young Conservatives. And, you know, the reason for that was the irrationality of waving little red books, which was the, you know, the thing at the time. And so we were...

Zierler:

People did that? People really waved little red books?

Lindsay:

Oh, they really did wave little red books. Oh, no, absolutely. No, no, no. I mean, it was full throated. You know whatever the socialist worker printed, was what you were supposed to do that day. And I found that obnoxious. It just doesn't jibe with the physics view of the world, right? And my wife was very similarly minded. And so we were very active both in the Federation of Conservative Students and in an organization for liberal, left wing Toryism in the United States, I mean in the UK, sorry. And those were the days before Mrs. Thatcher dragged the Conservative Party way to the right. And so I was extremely active. I ended up actually as a parliamentary candidate for four years.

Zierler:

Really? [Laughs]

Lindsay:

Yes.

Zierler:

So that was an entirely different life you could have led?

Lindsay:

Yes. So I was quite serious about it. I mean, it was something you know. We had a 40-mile drive to my parliamentary constituency every night in the fog along the Mersey River. And I had very little, of course, income as a graduate student and then postdoc. And most of it went to being a candidate. And so it was an exhausting experience. And, so I'm very glad I didn't stick with it and quit really at the last minute because the constituency went from labor to conservative. And I would have had a different career path, and I don't think I would have been very happy. [Laughs]

Zierler:

Now, Americans have some trouble understanding the exact parameters of these political debates in Britain, particularly how left the left can go right?

Lindsay:

Oh, absolutely. I mean, everybody with gray hair says, oh, my politics hasn't changed, the world changed around me. But I certainly find myself on the left of the spectrum in the United States without, I think, having changed my views too much, although I will say it's been a shocking revelation to me how active racism is in the US. I mean, it was it was present in Britain, too. I'm not preachy here, but it's sort of got a shocking violent edge to it here, a physical edge. And in Britain, you'd see seaside landladies would put cards in the window in the 60s saying "no coloreds". But this sort of physical violence against racial minorities wasn't there.

Zierler:

My sense is that, like with anti-Semitism, that it's more casual, also. It might not be as violent, but it's more casual.

Lindsay:

That's a very good summary of, I think, the way that many things are in Britain, yes.

Zierler:

Now, in terms of your politics during your undergraduate years, were you mostly focused on domestic issues? I mean, were your political views aligned in such a way that it would be obvious how you felt about the Vietnam War, for example?

Lindsay:

Yes, I think that's true. And so one of the factors in not considering a career in the States, because my PhD adviser wanted me to interview for jobs in the States. And one of the factors against it was, A, I didn't want an academic job, and, B, I thought the states must be a terrible place because of the Vietnam War. Life's more complicated than that, of course, actually. But, yes, I didn't leave a good impression. I will say, though, I remember going to my first overseas conference in Budapest, and that was the time when Hungary was communist, and spending time on the eastern side of the border and being surrounded by Russian troops. You crossed back into Germany with completely altered feelings about the American bases from when you left Germany to enter the Eastern Bloc.

Zierler:

So when you say Maggie Thatcher moved everything far to the right of what you had expected. Who were some of your political heroes during those days?

Lindsay:

There was a wonderful politician in the Macmillan administration called Ian McCloud. And Rab Butler, was another personality. This, you know, pragmatic centrist conservativism, and there's sort of good things about conservativism. I mean, you know, maintaining those institutions of state that give a country stability and so on. But then at the same time, being open to economic progress, to realizing that success for the business community is not necessarily success for the whole community. And that was the kind of angle we came from in the Conservative Party.

Now, having said that, the situation with trade unions in Britain was so politically bad, that with hindsight, Mrs. Thatcher, had to do what she did. And because I came from another direction altogether, I think there would have been too much friction. But looking at it with the benefit of historical hindsight, the situation had to change in the UK. And so a lot of what she did was good, a lot of what she did was terrible, too. But anyway.

Zierler:

Who is your dissertation advisor?

Lindsay:

Ian Shepherd. He was British, but he had done his PhD in the states at UCSD under George Feher in Solid-State Physics. And he came, he worked for E. I. du Pont. And he came back to Manchester because Sam Edwards, I've mentioned Sam to you before, wanted to establish a polymer physics group, and so he hired Ian and a couple of others to join the faculty at Manchester to get this going. Unfortunately, Ian died around the time I graduated. He contracted melanoma in San Diego from spending too much time on a surfboard. And he had actually accepted a job in the US, and the medical exam for his visa or for the job revealed that the melanoma had returned. So he died relatively young. So I didn't have any guidance from him when it came to the job market, all the sorts of things you're supposed to do as a post doc. But he was a really a marvelous guy.

Zierler:

What was your dissertation on? What did you work on?

Lindsay:

I looked at low frequency exhortations in polymers, building a Fabry-Pérot interferometer and loved instrumentation. So this was a pretty high performance Fabry-Pérot with automated control electronics and so on. And I did a lot of experiments on various polymer systems. I think the one that was perhaps the most informative was looking at the properties, at ultrasonic frequencies, of cross-linked polymers, rubbers, which we made by irradiating poly dimethyl siloxane. So I remember nightmares about being locked in the chamber with the cesium source that we put samples of PDMS in to cross link them. It was light-scattering studies of polymers.

Zierler:

And what was compelling about polymers to you?

Lindsay:

You know, to be honest, the choice of polymers rather than something else was twofold. First of all, I didn't want to do a nuclear or particle physics research thesis. Part of it was the fact that the broad support for that community came from the weapons development program, at least in the UK. And plus, of course, it's a large herd activity. I like solid-state physics a lot, but the final choice was simply because Ian offered me a jolly good salary.

And it turned out that learning polymer physics was very useful. I mean, it has fascinating aspects, but it's a tougher subject than solid state physics, because of the lack of symmetry operations and so on. And in those days, there was quite a disconnect between the sort of scaling theories that Edwards and DeGennes were doing and experiments that you could do. I mean, the two have come together, actually, but in those days, there was a disunion. So it hadn't the richness of a field in which theory and experiment interact as well as they do in other fields.

Zierler:

Now, to foreshadow ahead a little bit. Were you even aware of the term bio-physics? Was that on your radar at all?

Lindsay:

Well, another inspiring teacher comes into this, because the answer was no, of course not. And one of the professors that supervised my liquid helium experiment on tunneling gave me Watson's little book on the Double Helix.

And I found it absolutely captivating. I know it's not a politically correct book nowadays to get excited about it, but it's an exciting book to read.

Zierler:

It's also foundational.

Lindsay:

Yes. And I couldn't believe that a discovery as simple as this chemical structure, with its implications for genetics, that humans could do that. Again, a bit like the Bohr theory. And so that that was what made me interested in bio-physics.

The second element was when, by a tortuous route, I ended up at my job in the States, and I went to the department chair expecting to be told what to do, because that would be the case in a British university, right? And he said, I don't care, do what you want, it's your lab. And so although I'd had an interval working in Solid-State Physics for Philips, the electronics company, I thought, the heck with it, I remember this little book, The Double Helix. I want to do this, and apparently, I can. No one's going to tell me otherwise.

Zierler:

So now, when you've defended your dissertation, were you thinking about industry? Was that sort of the big plan for you not to go into the academy?

Lindsay:

So I was going to be a politician, right?

Zierler:

Right.

Lindsay:

And I was spending most of my time commuting to the constituency, you know, glad handing folks and pushing out obnoxious releases to the local papers and hoping they printed something and so on. And then, you know, rallying support in the Conservative Party to stop it going too right wing and so on. So, I mean, I spent most of my time every week on political activity.

So, at the time of my dissertation defense, I had absolutely no thoughts about a career. Now, my adviser died and I had a postdoc line. So I became the de facto head of the research group. I don't want you to read too much into that. All I mean is I was the guy who looked after the remaining students. And so I did that for a little while. The job with industry I had came about in a strange way. I realized I'd have to find myself a job at some point. And I wanted to stay in the north-west of England because of my constituency. And I had a couple of interviews during which it became clear the last thing they wanted to do was hire someone who might disappear off to parliament. So I wrote a letter to the then chair of the Conservative Party and said this was a real problem for a young candidate. And, bless him, he was on the board of Philips UK, and so they got me a really quite interesting job for a young person, which was in research Solid-State half-time and then as the company liaison to the unions. So, I sat in on all the meetings with the unions and took notes and so on, as a way of learning industrial relations. And so it was a very interesting time.

Zierler:

So what happened to your political career?

Lindsay:

I wasn't emotionally happy with it as time went on. Partly because it's a sales job and the idealism that you start with becomes consumed by the imperative of getting elected at all costs. I mean, that soon strikes one as sort of dirty, which is unfair because we need politicians. But I had a hard time, increasingly. And the straw that broke the camel's back actually was an esteemed colleague, he became a pretty prominent minister in Britain, who, when I was trying to make my mind up between taking the job at ASU and staying in Britain, had myself and my wife down to London to show us a good time and show us how wonderful the life of an MP was. And I remember saying to him, and I won't mention his name, but "X, it's okay for you, you know, you're well off, I'm not." And he said, oh, don't worry, he said, we'll get you a job on a few boards. And I thought at that point, I may as well be a prostitute. And that actually was the straw that broke the camel's back. And although ASU had no idea of it, up until that point, I had no idea whether I would accept their, by that time, very longstanding job offer.

Zierler:

What were some of the biggest lessons you learned during your time at Philips?

Lindsay:

A fear of bureaucracy. It was an intricate, arcane company with a Matrix style of management that goes in so many dimensions, you don't want to hear them all here. And so decisions were hard to take. And it was rather funny, it was a little bit like the army. The working professional career scientists on the ground knew how to manipulate the bureaucracy. So rather like the army, the whole thing was a bit of a standing joke. But it was great. I mean, they were a good company and had great people to work with. The other thing that was so interesting was the constructive relationship between labor and management. Philips had long worked to work with the unions. It did not have a history of conflict with unions. And that was good to see because the newspaper headlines in Britain at the time were all mass strikes and how terrible the unions were. And that was certainly not the case in a company like Philips. So, no, it was it was an interesting time.

Zierler:

Were you working in a scientific capacity at all?

Lindsay:

Yes, I was working in power semiconductor development, mainly in a lab in the north-west of England, because that's where I was based, but in collaboration with the main Philips Research Labs in Eindhoven. So I would spend time there from time to time.

Zierler:

Was it more like a basic science research environment?

Lindsay:

No, no.

Zierler:

It was not, it was all focused towards the bottom line?

Lindsay:

Yes, exactly. Well, that's the funny thing, actually. The company was bureaucratic enough that we had a thing called the Gamma program, which was to predict the profits that would accrue from a given research project. And I remember at the time my project had to go through this, saying to the manager responsible "But this is ridiculous, how do you know what profit's going to accrue from this?" "Oh, don't worry. I know how to stick the numbers in." Then the other thing, too, I think was a lack of enthusiasm for industrial research among British undergraduates and graduate students. And we all wanted to do our own bit of basic research. So in addition to the company driven development, everybody had something they were working on for a paper. And I did publish a few papers at that time. And it was really a bit silly because, you know, had I been in the States, I think the confluence, the congruence, between company goals and research would have been better understood, I think.

Zierler:

That's interesting. Now, looking ahead, you have many patents to your name. So, I wonder if you did learn a few things about how to bring a product to market.

Lindsay:

No, I was too young and too naive. So, I remember discovering patents relatively late in life and having some quite shocking experiences because of my failure to understand the difference between an invention that has utility and a creative piece of science. So I wish I had known then what I know now

Zierler:

And then, how did the of a position in Arizona, how did that happen for you?

Lindsay:

Completely and utterly fortuitous. As I told you, I wasn't greatly enamored of the US for not good reasons. I mean, well, I suppose the Vietnam War, right, prejudice? So, I was prejudiced.

Zierler:

It was a caricature that you had of the US.

Lindsay:

I had a caricature. I had interviewed several places in the US. Bell Labs among them.

Zierler:

Right.

Lindsay:

And I really didn't like it. I thought New Jersey was like a dirty version of Europe. Why would I be happy there? So it was completely not on the agenda. Plus, I did those things because academic colleagues wanted me to, not because my heart was in research. But my wife saw an advertisement in the New Scientist for Arizona State. And so my first reaction was, you know, I don't want work in the States.

And she said "But, yes, if you get an interview, it will be a free vacation there. And you've never been to Arizona". And she was very smart because she had worked in the States as a student and particularly loved the West. And I do remember getting off the plane and someone told me to go see the Apache trail through the Superstition Mountain. So I rented a car, the suspension of which I wrecked by driving the entire 300 miles of the Apache trail. Before I went into ASU, by the way. And I thought the Sonoran Desert was the most beautiful thing I had seen in my life. And I thought it was going to be just sand.

Zierler:

Right.

Lindsay:

And I could not believe the Sonoran Desert, A, and B, I was completely enchanted with the cowboy attitudes of Arizona. It was so orthogonal to the class system in Britain, so I fell in love with Arizona on the spot. And that's why I'm here.

Zierler:

That is amazing. [Both laugh] So I know, you know, looking back, you only have a grand plan after the fact. But clearly, Philips was not going to work out for you long term. So what did you think...?

Lindsay:

No, because I was a sort of a political hiring, that's right.

Zierler:

Yeah.

Lindsay:

And the expectation was that I would go on and be a constituency member of parliament, right?

Zierler:

Right. So absent the political career and absent the long-term career in industry, do you think that you would have ended up at a British university at some point or were you really not headed in that direction, absent this magical time in the desert?

Lindsay:

You know, I had given it no thought. And, I mean, this is hubris, I know, but, despite the fact that I had never put much effort into schooling, I'd never had a problem succeeding, you know, at something, getting a good grade or what have you. And, so, it just struck me that I was going to go with the flow, and, you know, whatever I did would work out.

So, no, I did not have a plan. I did not have a grand vision. And it was only coming to ASU, which wasn't the school it is now, and being told, well, you know, "do what you want to" and thinking, well, maybe this stuff that was in that little JD Watson book might be fun. And you know, I had a total grand total of sixteen thousand, one six, startup money as a salary of sixteen thousand a year. And I was in hog heaven.

Zierler:

Yeah. So it was biophysics from the beginning, once you were ASU?

Lindsay:

There was a very strong, solid-state physics program, so I leveraged that to do quite a bit of solid-state physics to begin with. What I was really interested in was I had encountered some theoretical work on the importance of low frequency modes in DNA. Very naive, I can't believe that I didn't have a deeper understanding, but I didn't at the time. But nonetheless, it was interesting theoretical work, and so I was going to use my experience of measuring low frequency modes in polymers to look for vibrational modes in DNA. And to do that, I had to build the world's best Fabry-Pérot interferometer, and I really did.

I remember the crew from Bell Labs arriving in Phoenix at an American Physical Society March Meeting in the 1980s and standing in my lab with their jaws on the floor saying, "Can you believe it? This beautiful instrument in the desert." But I mean, it surpassed anything for resolution that was it was out there. And so we did quite a bit of work on things like phonon fluctuations and sorted out a mystery in the literature, in which we understood that for large Q-vectors, in other words, back scattering, you study interactions between pairs of phonons, whereas if the Q-vector gets smaller and the spatial distance longer, you then approach equilibriums thermodynamics. That was a really fascinating piece of solid-state physics. So we did a few things that were really fun and interesting, but the whole goal was to look for low frequency modes in DNA. And so that's where things took off, really.

Zierler:

How do you account, for a tiny budget in a department that was not particularly known for these things, for creating instrumentation that knocked the socks off of some of the best laboratories in the world? How does that work?

Lindsay:

Hard work, but not hard work in the sense of flagellating myself. But I do remember when I was an assistant professor, I would work seven days a week and I would put in a few all-nighters every week, not because I felt a pressure for tenure. I didn't even know what tenure was, I mean, I wasn't part of the US system, but I just wanted to get this thing working.

And it was very interesting because the graduate students were not the same type of self-starters that you would have gotten at a more prestigious university. But they got caught up in the enthusiasm of the project. And what was wonderful about it was, you know, being caught out with making a stupid mistake in the design somewhere, and this graduate student, who you had thought was slow saying, "I'm not sure it works like that". And I mean, so you know, my point is that you don't need wonderful talent if it's a team and there's enthusiasm for a goal.

The second interesting thing was, ASU had John Cowley, who's one of the pioneers of atomic resolution electron microscopy. So they had hired the best instrument makers out of Motorola, which was based in Phoenix then, or Chandler. And they had built a fantastic mechanical instrument shop. So these guys could do absolutely wonderful things. And in fact, it was a great training because I knew in order to get the performance I wanted, then I pretty much had to control the optics at atomic level precision. So by the time Paul [K.] Hansma and scanning tunneling microscopy came along, I knew how to build an instrument with atomic precision control.

Zierler:

I want to share with you because maybe this will give some insight into some of the secret sauce at ASU. I spoke with Frank Wilczek a couple of weeks ago.

Lindsay:

Oh, yes, Frank. Great guy.

Zierler:

And he has, you know, he has this incredible affiliation with ASU.

Lindsay:

Yes.

Zierler:

And I asked him it's, you know, like of all places. It's not like he's a man without portfolio, right...?

Lindsay:

Right. [Laughs]

Zierler:

Why ASU? And he said because ASU is just, they're open to anything. That it's a place where people think big, and if you make a good case about something, the right people will say yes at the right time. And I wonder if that was your experience as you were beginning to chart your own research agenda at the beginning of your career.

Lindsay:

Very interesting, because, of course, A, I am not a Nobel Prize winner. And B, that was ASU many years ago. But actually what Frank, you quote Frank, as saying, is exactly what I would say about ASU today. It's what I say to some of the wonderful young hires we make, I mean, with, you know, competitive offers from Ivy League schools and they opt to come to ASU. But funnily enough, aspects of what Frank said were true all those years ago.

Zierler:

And I got that sense. This wasn't a new thing. What he was saying was that this was like the culture and a culture doesn't happen in a year over a presidential term.

Lindsay:

Well, our president, I guess he's been here since, what, 2002, something like that. And so it's a very long, long lived presidency. He has not let up one ounce of energy, is just as creative today as he was when he came. So he has transformed the culture to a large measure. But he came to ASU from Columbia because of these characteristics that you're talking about. And they did exist.

So I had interest in amorphous materials, and there was a very strong solid-state chemistry group. And I remember as a brand-new young assistant professor, wonderful evenings with drinks and pizzas at a quite a famous solid-state chemist, Alexandra Navrotsky's, house. We used to meet once a week and we'd spend the whole evening reviewing papers on properties of amorphous materials. And, you know, it was a love fest. And so, the community was amazing. The chemists talked to the physicists. And it was true, if only because ASU was so new to research, there were no previous prejudices built in and no barriers.

So to give you a for instance, we needed a biochemistry lab from day one. But I had my standard lab space, so we just emptied one of the janitor's closets that had a sink in it and turned it into one. Didn't ask anybody. [Both laugh] Another, for instance. I remember that facilities was taking a long time to sort of plumb and fix my lab up. So in the end, I went to the local hardware store and I did it myself. And I do remember being in my underpants painting the optics room black because I didn't want stray light, and the guy from facilities coming in and saying, "You can't do that". And I said, "Well, you're not doing it." So they moved in the next day and finished the job. But the point in all those stories was that there were no obstacles.

Zierler:

Not even funding obstacles at some point, after you proved your mettle?

Lindsay:

So, I mean, there was external funding, of course. The interesting thing was, almost as soon as I arrived, I had a little grant from the Research Corporation. And they then wrote to tell me that my grant had been bought out by Schering-Plough Corporation. And I thought, good, they must really like it. So I wrote a letter saying, can I have some more money then?

And they came back and said, no, our referee says it's time for you to go to the feds. And I'll tell you another interesting thing about ASU at that time. I went to see Dick Work, who was the chair of the physics department, and I said, "Dick, I've got this letter from the Research Corporation and they want me to go to something called the NSF. Do you know what that is?"

Zierler:

That's great. Stuart, did you feel like you were in Empire Building mode? Were you looking to gobble up as many graduate students as you could because more students mean better research? Were you that kind of professor?

Lindsay:

I mean, I did have a very big group, but it was that people glommed on to the lab. So my star student, who's just died very tragically, but my star student had come to ASU to do astrophysics. An interesting story, he came near the top of the CUSPEA exam, but didn't think he was going to. And so he thought "I'd better choose university I've never heard of." And Arizona State begins with A. So I had this brilliant student, he was the most brilliant, but I had a number like him and they were just a great team.

So we would all go to the APS meetings together. And in those days, we'd all go to every talk that was remotely connected with anything of interest. And it was just an amazing team, they were really great kids and we keep in touch. And we were actually going to have a reunion at this March APS had it not been for Covid. So, no, it wasn't a deliberate empire building at all. And if anything, I've sort of worked in the opposite direction, particularly as I've gotten older and more aware of mortality, because I've advised students of faculty who have taken jobs elsewhere or who've unfortunately maybe died. And it's a very bad situation, so I I've not wanted to be in a situation where I have had students, you know, unmentored. But no, it wasn't an intention to build a big group at all. It would be a new project of interest, a new grant. And there were always students wanting to join the group.

Zierler:

So as a matter of developing this intellectual trajectory from this little book that had transfixed you earlier to these remarkable instruments that you were building. What do you think were the most important research questions that you were after in those early years?

Lindsay:

So I was very naive. I thought that I was being very clever and thinking, well, I know the speed of sound in a solid, and I know the size of a biological molecule. So these must be the important modes. Of course, folks who know Kramers reaction theory actually know, of course, that only tells you something about an attempt frequency. But I thought I was going to discover, you know, a whole vista of new things. But interestingly, it did lead to a completely new area for me because one of the problems I wanted to look at was non-equilibrium phonons in DNA. And I was pushed to the free electron laser at Santa Barbara. I now realize by political forces, because they had built it for the Office of Naval Research, had built this incredibly elaborate instrument. And then somebody pointed out to them that it wasn't going to shoot down Russian satellites when it's cloudy. And so the instrument was going free, and they were desperate for a proposal, so I got this large proposal funded to do non-equilibrium phonons in DNA.

And the main thing to come out of that was, because it was at Santa Barbara, going to Santa Barbara, meeting Paul, who after my talk about what I was going to do on this multi-million dollar instrument (and my talk was riddled with Greens functions and blah, blah, blah) Paul comes up and says, would there be any interest in imaging this DNA molecule in water?

And I think, who is this guy? He must be insane. And so I go to his lab and see a scanning, tunneling microscope imaging graphite atoms underwater. And that's it. So, you know, that's the beginning of the nanoscience story. Actually, now, in going into nanoscience and thinking about the statistical mechanics of small systems and emergence, and I now realize there are very powerful themes across biophysics and emergence. But no, I didn't go in with that knowledge at all.

Zierler:

Did you have a strong background in statistical mechanics as a graduate student?

Lindsay:

No, not really. We all took stat mech, including a graduate course. And I liked it, I mean, it was a it was a subject that I enjoyed. But it hadn't sunk in at a deep level, it was sort of as more or less a set of formulae that if you were lucky, you'd remember to use them. And it's only in later years, appreciating the role of fluctuations in biology, that stat mech becomes everything.

Zierler:

And in terms of biology, now, when you start to get into nano issues, what are you doing now? Are you teaching yourself biology or are you learning it on the fly? Are you relying on your students? How is this working for you?

Lindsay:

So that's the interesting thing, by the way, you talk about relying on students. I mean, I relied on the students as intelligent critics. But I always, if I've gotten into a research problem, I've always done my best to try to master the topic, right? And, you know, independently by reading papers or whatever. Biochemistry was hard. So I did take the biochemistry graduate class when I got my first NIH award. And it was really an eye opener. I think I mentioned to you that I was teaching classical mechanics from Goldstein, actually. Goldstein's, what, 50 years old as a book, probably more than that now. And in the graduate biochemistry, there was no textbook. We read papers. It was just amazing. And I can tell you now that a lot of what I was taught was wrong because the field changes so quickly. But I also had good colleagues. I mean, people I could go talk to at ASU who were always very communicative.

Zierler:

So there was a good spirit, a spirit of collaboration at ASU?

Lindsay:

Absolutely always. And the in chemistry department, I think particularly so.

Zierler:

Now your home department was the physics department?

Lindsay:

Yes, absolutely. I started in physics. I wanted to teaching chemistry just to, you know, broaden myself. And plus, I have such good colleagues in chemistry. So I did at a later stage, get a partial appointment in chemistry and for a little while I taught the freshman chemistry, which was wonderful. Probably most of our colleagues have done physics demonstrations in lectures. But I promise you that before fire marshals became little fuhrers, chemistry, freshman chemistry demonstrations were absolutely the best. [Both laugh]

Zierler:

Now, as you honed your identity as a biophysicist, did you remain thinking that the physics department was the best place for you or that really wasn't an important consideration?

Lindsay:

That's interesting. When I started, it was the usual, "This isn't proper physics."

Zierler:

Right.

Lindsay:

And I think there was hostility to it. They made their next hiring in biophysics the year I went on sabbatical which tells you something, right? But you know, ASU now has, I'm pretty certain, the biggest biophysics group in the United States. And I mean, it is just an astoundingly good group. It has a distinct flavor. And the distinct flavor comes from the fact that it's close to physics. And so to me, it's remarkable how the thinking about a problem compared with what might happen in a, you know, what's called a biophysics department in a medical school compared with how physicists think about biophysics, there is an enormous difference. Now, there's a downside, which is the physicists often don't think about the practical consequences of what they're doing and how that's going to help them get NIH funding. And like, you know, to be abstract for the sake of it. But, actually, biophysics is so complex, there are wonderful opportunities to address some of the most fundamental questions, while at the same time writing a proposal that a panel at the NIH are convinced is going to help attack some disease or important bioengineering problem.

Zierler:

Now, now that you mention NIH, I did want to ask, at some point, did you sort of get self-consciously interested in conducting research that would be medically relevant?

Lindsay:

No, my interest has always been basic. But it took me a long time to get confident enough about the problems I was working on to then start thinking in terms of the link to medicine. So, I mean, it dawned on me after many years that the key to understanding gene expression is chromatin structure. And so I actually ended up in a collaboration with the National Cancer Institute where, of course, gene expression is everything. And so rather indirectly, then, cancer became the sort of driving disease force in that research. But the basic interest there was the sort of physical mechanisms of control of gene expression.

Zierler:

When did you get involved in atomic force microscopy?

Lindsay:

Oh, that's Paul Hansa to thank for that.

Zierler:

So it was right at that formative moment when he came up to you?

Lindsay:

Oh, yes. So, I mean, the way that worked was, of course, I was there to do this experiment on this huge free electron laser and he took me up to his lab and his graduate student, Richard Sonnenfeldt, was operating one of Paul's STM's in water, and that was it. I arranged to fly back within a few days and spent a week or so with Richard, actually, it turns out, successfully imaging DNA molecules under water, although the experiments were very hairy and never published. And then went back to ASU and just had to build an instrument. And actually another comment on ASU is, of course, I was bursting with excitement about this new field and collared every darn colleague I could to show them our initial images. And a delegation of them, bless them, went with me to the very first vice president for research (ASU had never had one). And they said, this is really exciting, you've got to give Stuart some money. And he did. So I had my first STM operating in water in a couple of months.

Zierler:

And what was it about water as a medium that was so compelling and interesting to you?

Lindsay:

So it started out, of course, because biological molecules function in water, and, in fact, fold as they do fold because of water. So water is the driving force. The hydrophobic bits stay on the inside, the hydrophilic bits point out towards the water molecules. So water's everything. What dawned on me then, and this is really interesting, this is something that I still don't think is widely appreciated except by a pretty specialist subset of the community: By using the right approach to purifying chemical reagents and by using very careful electrochemistry, you can control an interface between an electrode and water with atomic precision. In other words, careful enough, electrochemistry is almost as good as ultra-high vacuum physics, which is sort of an astounding thing, but it's true. And the problem with electrochemistry, I remember when I used to referee for Surface Science and they brought out this issue 30 years of Surface Science that they gave to the referees. And it's really interesting because when the journals started coming out, A would write a paper saying, well, B's results are all contamination and so on. And then with the invention of those wonderful copper gaskets that sealed new UHV systems, suddenly all the labs started agreeing with one another. And so, you know, if good electrochemical practice was widespread, I think you'd see it much more widely used in the physics community because of the gorgeous interface between chemistry and physics.

So we did quite a lot of work on electrochemical control. And this brilliant student I had who unfortunately has just died, came back to my lab as a postdoc and cherry picked some of the best problems in electrochemistry and solved them on a scanning tunneling microscope. So he had some outstanding publications when he was in my lab, and he then went on to his own faculty job.

His most astounding publication, in my view, was done when he had no graduate students, all by himself at a fairly minor school in Florida and it won him a major prize. I mean, just beautiful work. So this interface between electrochemistry, surface science, and nanoscience is a really nice place to work, and we still use it in biophysics to this day.

Zierler:

Now, when you talked before about gaining confidence in terms of your research and its potential applications to medical issues. How did that how did that play out? How did you know that you were really onto something and that you were able to share this research with people who might be able to apply it in the clinical setting?

Lindsay:

So I think in the example I gave you of chromatin, it's such a hard problem. We still, after all these years, haven't made progress that would justify that confidence. And in fact, I think no one has. I think the issue of chromatin structure is still an open issue. But I can give you a more concrete example of where we have made progress. I was very interested in molecular electronics stemming from the fact that I remember actually talking to the famous Ivar Giaever, Nobel Prize winner for tunneling and telling him we were trying to image DNA with a scanning tunneling microscope. And he was a very blunt guy, and he told me what he thought of that idea. And it's certainly true, if you take a typical vacuum decay length for an electron from a typical Fermi energy, of sort of an angstrom or something, then going through 20 angstroms of DNA is outrageous.

And so, you know, that got me thinking about electron transport molecules, tunnel transport and other types of transport. And so, eventually, because of that, I think my most highly cited, well not actually, but second most highly cited paper, is on making electrical contacts to molecules. And because of that, I got to referee proposals that set out to use electron tunneling to sequence DNA. So I got into this as the cynic designed to turn these proposals down, and then thought, well, maybe there is a way to do this.

So I've had many, many years of funding from the National Human Genome Research Institute. And there is a very simple connection between physics, right. You're inventing a new way to sequence DNA. You lower the costs; you increase the clinical impact. I mean, the impact of sequencing is now widely known. And so I've been with that program for many years. And I think finally, after a number of years that I would be embarrassed to admit to, given that the taxpayer has been supporting me, I finally think we actually have a breakthrough that may well change sequencing. So that's sort of the example where some very direct connection between new physics and a medical outcome.

Zierler:

Who, besides Paul, had been some of your most productive collaborators as you increase your reputation in biophysics over the years?

Lindsay:

I had a wonderful and instructive collaboration with Gordon Hager at the National Cancer Institute. He runs a laboratory for chromatin and gene expression. I had a good, oh, age is getting to me. But anyway, his postdoc's name, Yamini Dallal, who's now at the NIH, wonderful interactions with her.

Zierler:

Do you know Kier Neumann at NIH by any chance?

Lindsay:

I've seen his name, but I don't know him. So, you know, on the atomic force microscopy side, Peter Hinterdorfer at the University of Linz. Peter and I've worked together a lot. In fact, AFM was the main thing in the lab, AFM and STM. And Peter came out to Arizona using a technique we had developed for controlling the amplitude of oscillation of an AFM cantilever very precisely, to develop what we call "recognition imaging", which is a very cool technique in which you put an antibody on the end of a cantilever with a flexible tether, a little piece of polyethylene glycol, and you control the amplitude so that the tether is just fully stretched at the upswing. Now because the cantilever is highly over-damped, it's not like a harmonic oscillator. It doesn't remember what its amplitude was down here, it's just as far as you drive it. And the technique we invented called "MAC Mode" drives the cantilever with complete precision. So what you see is that when the antibody binds to something, and you stretch the PEG tether, it decreases its top amplitude. So now, by separately putting the top and bottom amplitude into two different channels, you can map both the topography and the chemistry of the surface.

Very powerful tool. Peter in particular has used it to do a lot of wonderful things. We haven't focused on it so much. It's not in widespread use because to understand it, you need you need the right instrumentation and then you have to do all that surface chemistry on your AFM probes. So it's not been widely adopted, but where it has been adopted, it's producing sensational results. There are probably five or six labs using it, but it's hard. I forget where that question, where that answer came from originally. Anyways.

Zierler:

The collaborations.

Lindsay:

Oh, mentors, mentors, collaborators. Peter's been a longtime collaborator. Another person I think I should mention, is years ago when AFM started, there was a little startup company. We didn't know what patents were as I mentioned to you at that time and they simply wanted to come and use the technology from the lab and commercialize it. And my attitude in those days was, go ahead, guys. No agreements, no patents, no royalties, no nothing. And so they built an AFM company and they had a senior engineer who was a physics graduate of Princeton. Wonderful guy. Anyway, this company, Angstrom Technology, went broke for all sorts of very good reasons. And I saw Tianwei wandering around the halls looking starving, which he was. He had been unpaid for a long time. And I managed to scrape enough money together from grants to give him a very poorly paid postdoc. And Tianwei was a magic pair of instrumental hands. I mean, I thought I was good at building instruments. Tianwei was, you know, on another plane altogether. So Tianwei and I founded the company Molecular Imaging. So, you know, he was a big influence.

Zierler:

I'm curious how that works in terms of starting a company within the context of your professorial engagements. Do you do you take a leave of absence? Do you have to talk with the lawyers in terms of intellectual property? How do you work all of those things out?

Lindsay:

Well, once again, this is the wonderful ASU, laissez faire, right? So we did at that point have a patent.

Zierler:

On what? What was it on?

Lindsay:

It was on electrochemical cells for scanning tunneling microscopes. And, so, I went to see the tech transfer guy and I said, "I can't pay you any money". And he said, "Oh, that's all right, give us three percent of the company". And it turned out this was totally illegal because at that point, the tech transfer office wasn't distinct from ASU and ASU was a public university that can't engage in commerce, right? But you know, who knew? [Laughs] So we had an agreement that we would pay them so and so much. And then we just used a credit card and built the first instrument in the back bedroom of my house. And then, interestingly enough, that actually took off. People wanted those instruments. And so not long after that my present business collaborator came around looking at business opportunities at ASU. And so he came to see me about that company that when bankrupt, Angstrom Technology. And he said, well, you know, do they have any interesting property? And it turns out I'd been in this tech transfer guy's office that afternoon because of the new company we were founding, when Virgil Elings, who was the head of Digital Instruments had called up saying this is really interesting work out of ASU and can I license a patent?

And I heard Gary argue, saying to Virgil, no, you can't. It's not ASU's intellectual property, it belongs to this little company. So I told this to my business colleague, Bill, and he went and sought out the remnants of Angstrom Technology and said, if you file a patent within a week (because the anniversary was coming up), I'll give you X for your company. And if you get the claims granted, I'll give you Y. I don't know that I ever knew what X and Y were. But all of that panned out. So Bill got this patent, we started our little business, and then Bill said, I'm going to buy your company. So he bought Molecular Imaging for shares in Gatan, the parent company. And then, you know, that snowballed from there. So I never had to worry too much about the business side. I did take a six-month sabbatical to get the premises and labs and the hardware side of the business going, but that that was it.

Zierler:

What exactly was the product that Molecular Imaging sold and who were its clients?

Lindsay:

So STM and AFM, but with a focus on electrochemistry chemical interfaces. So, you know, we weren't trying to compete with Digital Instruments or the general AFM market. I mean, of course, if somebody wanted one, we were happy to sell one to them. But the main thing was driven by this powerful realization that electrochemically controlled interfaces are great places to do science at.

So it's rather nice these days. I still meet people at meetings who say I did my PhD or one of your instruments. They sold all over the world, you know, many hundreds of them and a lot of good papers were produced on them. It was very satisfying.

Zierler:

Did they have a commercial use as well where there was simply something for more academic oriented laboratories to use?

Lindsay:

Mainly research, although a few sold to pharmaceutical companies. The AFM's that were, you know, not necessarily for electrochemistry sold to semiconductor companies and so on. But that market was dominated by Digital Instruments. Mainly we sold to researchers.

Zierler:

Now, did you step back from the company at some point or are you still involved?

Lindsay:

No. No. So the company was, as I said, taken over by Gatan, and I actually was the boots on the ground for the facility in Tempe. And my then business partner, Bill Offenberg, myself and Tianwei (the hungry postdoc I took on) were the founders. And it was actually a wonderful thing because what I did was, I said to Tianwei, "Well Tianwei, if I put up the money to found a company, you only have to pay me back if the company actually ever makes some money."

Zierler:

That's a good deal.

Lindsay:

Blow me [Laughs] Tianwei payed me back. But so Tianwei and I were the sort of scientific founders, Bill Offenberg was the business guy. And so the company, then part of Gatan, was sold to a company, Roper, in the post-2001 era. Roper decided to sell everything off in technology, and the then CEO managed a management leveraged buyout, so it went back into our hands again. And then, I think in 2006, the company sold to Agilent. And so at that point, I would consult for Agilent for a while, but at that point I was out of it.

Zierler:

In what ways had the company changed since your founding days?

Lindsay:

Oh, of course it got much bigger, more professional. Agilent did a pretty good job, but then Agilent spun out Keysight instruments and Keysight wasn't terribly interested in that. It decided it was going to be a nano measurements division. So it took on a number of products that were just, you know, if it had been my choice, I would have said disastrous from the get go. Like a table-top SEM that was very, very clever with micromachined lenses and things in it. And it really did look about the size of a hot plate you you'd use to cook a meal on. So very clever, but the cost of manufacturing, it was more than the cost of buying a conventional scanning electron microscope.

And there were a number of product decisions like that that I could not understand. So that division got driven into the ground. So the company still exists, but only to service existing equipment, it's not it's not selling microscopes now.

Zierler:

Now, shortly after you step back from the day to day, you became the director for the Center for Single Molecule Biophysics. Were you also its founder? Has it had a preexisted you as director?

Lindsay:

That was an interesting set of events, too. Michael [Crow], when he came, had this vision for the Biodesign Institute. And I was on my way out, actually. I had a wonderful offer from Michigan, but interestingly enough, the more time I spent up there, the more I realized the benefits of ASU and Michael have somehow devined this. I hadn't told anybody at ASU that I was looking at another place and he offered me the directorship of one of the founding centers of Biodesign as a way of retaining me. But I was also involved in the discussions about the design of Biodesign, which was fascinating, and it's achieved many of those goals. So I was one of the first directors and I think I'm the sole standing founding director, actually, at the institute. So I've continued to do that over the years. We had a number of faculty. We shrunk because as faculty, like my colleague Hao Yan, have gone on to become very famous people, they now had their own centers and quite deservedly so.

Zierler:

What's the significance of the name? Of all the things that you've been involved in, what does single molecule biophysics connote?

Lindsay:

So, of course, it was exciting in the world of nano science to think about measuring the properties of single molecules to gain insight into how proteins function, proteins and DNA. But I now realize the story is actually, you know, there are layers of emergence. So for me, one of the most interesting problems at the single molecule level is the mechanism of enzyme catalysis. Fascinating problem. And it's definitely a problem in emergence.

So the theme of my book on nanoscience is that there is a common theme throughout, actually throughout nature, that assemblies of things of small number, be they, you know, 50 water molecules around an electron transfer molecule, or 100 water molecules around a protein, are complex enough that the degrees of freedom are very high, but also small enough a number that the relative fluctuations are enormous. So there's a magic point where you can drive a transition to a state that would be a very rare state. So, for example, the final state of an electron transfer reaction or an enzyme catalysis (it's also an electron transfer reaction, but with many more steps). But it all comes about from this beautiful balance between having enough degrees of freedom to be able to sample a space that contains this rather unique end point, but being small enough that you're not in a thermodynamic limit. So a highly improbable state is quite probable.

Zierler:

What does it mean to be in a thermodynamic limit in this context?

Lindsay:

Large number of particles. So that the measurements you make at any one point of a parameter like, you know, internal energy is the same everywhere simply because you're sampling enough atoms and molecules.

Lindsay:

However, you know, it's root N over N. And when you get to the point that root N over N is on the order of unity, then the fluctuations are enormous. And so the probability then that some system will go into an unlikely state is no longer small. And so you need this balance between having unlikely states available and large fluctuations. And so this is a theme not only amongst single molecules, which is what I've been studying for the last several years, but among biology as a whole. So many of these ideas will apply to things like cycles in predator prey relationships, for example. So biology is a fluctuation dominated subject. And what I'm finding beautiful is that there are commonalities across all length scales in terms of emergent phenomena. So my expertise is with single molecules and I'll probably go to my grave doing single molecules because it's what I know. But there is this commonality: a single molecule is a complex system already, especially when it's in the bath of water molecules.

Zierler:

Now, when you're emphasizing commonalities, what's a really good example to illustrate the point?

Lindsay:

Well, I just mentioned predator prey relationships which rely on fluctuation statistics in small populations of antelopes and tigers, just as electron transfer relies on a small population of water molecules generating the polarization necessary to get the transition to state for electron transfer. So those are what I mean by the commonalities.

And in my nanoscience book, I actually end the book with what I think is a beautiful example of a gene that has, I think it's thirty-two thousand or sixty-four thousand, I can't remember, splicing variants and it's a gene for one of the adhesion molecules that holds neurons together. And the [research] team asked themselves the question, why so many splicing variants? Just to interject, you know what a splicing variant is?

Zierler:

Yes.

Lindsay:

Okay. So why so many splicing variants? And so they diminished the complexity of the gene and the poor old fruit flies with the diminished complexity of the gene developed pathologies in their neural network that couples to the bristles in their ear which is where this gene is active. And so this is exactly the opposite of the Divine Watchmaker view of the world. This is saying that if you give the watchmaker, a drawer full of random gears and shuffled the drawer, you'll get the right result. If you take some of the random gears out, you won't be able to access that unique state that fluctuations drive a biological system to. And so, you know, I start the book with talking about fluctuations in electron transfer, and I end the book by talking about fluctuations, driving the assembly of brains, and, you know, perhaps even ultimately consciousness. I wouldn't know. But I think it's a common theme across nature. And not something physicists think of because we like to be so deterministic.

Zierler:

Were you inclined to be suspicious of intelligent design even before this research?

Lindsay:

Oh, of course. Yes. Yes. I mean, I have to say, in fairness, the school from which I was expelled was very religious. And so that naturally settled on antipathy, right? [Laughs]

Zierler:

And in more recent years, you went back into industry. Can you talk a little bit about Recognition Analytix?

Lindsay:

Yes. So there's an interesting story there. We had technology, an earlier version of technology for DNA sequencing based, in fact, on electron tunneling, and Roche licensed it. So Roche had a program for a number of years to try and develop this as a commercial product. And I was more excited, because to me, DNA sequencing is a commodity already. I was more excited about the idea of applying it to sequencing things like single protein molecules or even more importantly, sugar molecules. They're outrageously difficult to sequence in biology, and Roche was not interested at all. So I said to our head of tech transfer, "Well, when you write the contract, write it for nucleic acid applications only". And he did, and Roche said just fine. So then myself and a business partner licensed the technology for all other applications. So we kept the company brewing along without too much success for quite a number of years, basically generating patents. And now that we have technology that I think is going to be successful in DNA sequencing, I hope so, Recognition Analytixs now possesses that, and I'm hoping to see the company take off as something quite impactful pretty soon.

Zierler:

Oh, wow. So it's on the way.

Zierler:

Okay. Okay. Can you talk a little bit about how you've applied nanoscience to the energy issue?

Lindsay:

Yes, I had a little bit of experience with that. Not very successfully, I should say. So I mean, we've looked at things like electron transfer on an electrode surface between molecular systems and light harvesting complexes. Yes, involving things like photonic resonances and gold particles and so on. They've been published papers with a reasonable number of citations, but they haven't impacted the energy industry, and I feel I don't I don't know enough about that subject to be able to pick the right problems.

But what is interesting about that, is being aware of the need for control of structures on a mesoscopic scale in order to realize photonics, and coming across a new young member at the time of my center, Hao Yan. Hao and I designed photonic structures or generalized scaffolds for arranging molecular components over nano to meso scales. And, so while I haven't been terribly successful, I mean, our experiments worked. And I think there was even a maybe even a cover of Science. I can't remember, certainly a Science paper. Hao has gone on to just dominate this field and has done wonderful things.

Zierler:

What remains to be done with DNA and protein sequencing that compelled you to look at the issues in this field?

Lindsay:

So in the case of DNA, I have to say, I think it's largely a commodity. It's so cheap now, it's incredible. But there is a need for long sequence reads of high accuracy. The nanopore techniques that are out there are not highly accurate. My nanopore friends are going to throw something at me for saying that. But if you look at the data, they're really not. So there is a need for long sequence reads so you can assemble genomes accurately, so you can sequence through homo-polymer and repeated sequence, which are very frequent throughout the genome. Very large portions of it that haven't been sequenced. So there is a need for better technology and certainly cheaper technology because ultimately, we're all going to want to be sequenced for sure. That's DNA, now in proteins...

Zierler:

When you say we're all going to want to be sequenced? Why is that?

Lindsay:

Oh, because that will become your medical footprint, right? So in diseases like cancer, your genome actually changes in all sorts of complicated ways, so if it became facile, as indeed is happening now, to sequence tumors, if it became facile to do that for long ranges instead of just looking at certain target sites as they do now, I think a whole new book would open.

Zierler:

When you say facile, what does that mean in this context?

Lindsay:

Oh, facile would mean, you know, tens of dollars to do a whole genome. And to do it all in an hour, let's say. And, you know, I would hope, I mean, at least in the proposal we wrote to the NIH, we put numbers in to convince them that this may be possible with what we're doing right now. Now, in the case of proteins and other molecules and in particular biological sugars, the reason for doing proteins, which I think now the NIH has understood, but for years I've written proposals and they've always had terrible success, they've always refused to review them. The reason for doing proteins is because the many modifications of the individual amino acids are critical to the function of a protein. And when you do something like mass spectrometry, you average out over a population, or you have to isolate some part of it at enormous expense, in sample prpearation. And so you really don't get any idea of the heterogeneity of individual protein molecules, wherein lies their function. So, there is a strong argument for a single molecule protein sequencing. All my proposals came back with, "We have mass spectrometry, why would we be interested in this?" So I've given up writing proposals on that field, but am very well-funded for DNA sequencing. More importantly, though, and I think very obviously so, is the case for biological sugars. The only way of sequencing those right now is NMR. For NMR you need milligrams a sample in pure form. Very, very, very hard to do. And so we think we certainly with our recognition tunneling approach, we had a viable way of, when we published on that, of sequencing, at least linear sugars. And we now think we have a new enzyme-based technology that will do that.

Zierler:

And what's going to change as a result? What will this be beneficial to?

Lindsay:

So sugars in particular, and it's partly true of proteins because it's the old thing about looking under the lamp post where the light is. In the case of proteins, we know about all the common proteins, but not about the very rare ones because of this problem of not being able to solve the single molecules. In the case of sugars, it's even worse. Glycol-biology is regarded as the most arcane area of biology, and part of the reason is that you need very large samples of pure material and you can't look at variations. Now, where does this matter? Well, antibodies generally recognized the glycosylation on the surface of the cell. And, so, where glycosylation goes wrong can lead to antibodies not working, it can lead to drugs working the wrong way. So there was a famous case of an immunotherapy for allergic patients that actually caused deaths when the glycosylation state of the antibody that was used was erroneous. But for many of the problems not very much is known about it, because the research is not there.

Zierler:

You mentioned earlier that, you know, just to bring the narrative up to the present day, that you're actually working on coronavirus issues now.

Lindsay:

Yes, yes, yes.

Zierler:

In what way?

Lindsay:

So we have a new technology, which my business partner labeled DEMP, and he hates the word, "direct electrical measurement on proteins", but I use it because it's good shorthand. We discovered a few years ago that if you make the right kind of chemical connection to a protein so that you can access the hydrophobic core of the protein, proteins are fantastic conductors. They're much better than any molecular wire that's been made by human chemists. And so that's actually what our new DNA sequencing technology is based on. We wire DNA polymerase molecules into junctions and we look at the changes in the conductance of the enzyme as it goes through the open to closed transition that signifies the incorporation of bases. So in the case of recognizing COVID genomes, there's already a technology in existence to use CRISPR associated proteins, so called Cas or CRISPR associated.

And the way this works is you program them with a guide RNA that's complementary to the sequence of the viral gene, in this case. And then there are various ways in which they are read out right now, which of course are optical. There is one electrical way that's very inefficient. What we've been working on is wiring a Cas protein, just like our DNA polymerase, into a chip. And what we've shown in preliminary measurements is that there is a distinct change in the electronic state of the Cas when it recognizes a target sequence. So we think it should be possible to produce a single molecule detector. So this is no longer millions of molecules and an antibody-based test or a cleavage-based test. It'll be a single molecule, or actually an assembly of them, so you can look at the kinetics of recognition in a chip with a direct electronic readout. Should be faster, should be much more sensitive. And, of course, being infinitely programable by the guide RNA in a repurposed for any new pathogen. So I just saw today that our proposal to reach to make the chips got almost perfect score, so someone believes this. [Laughs]

Zierler:

Oh congratulations.

Lindsay:

Yes. [Laughs]

Zierler:

One of the things that's exciting right now, if we want to look at the positive side of things with coronaviruses. You know, across the globe, the level and intensity of scientific collaboration that is singularly focused on defeating this thing, it's a pretty remarkable thing to behold, right? And so if the end goal is, you know, either therapy or a vaccine, right? Because it's all it's all geared towards even the basic science understanding, it is obviously geared toward a very real objective, right? What would you see as your part in that in this global effort?

Lindsay:

So some sort of universal pathogen detector. But I have to say, it's very interesting because it goes back to a problem that has plagued me for years, which is places like the Biodesign Institute and of course the Broad Institute at Harvard are set up to develop ever more elaborate diagnostic and research tools. And yet the truth of the matter is if we had a simply functioning public health system in the United States, we would save many more lives.

Lindsay:

So the truth of the COVID epidemic...

Zierler:

You're sounding like a politician now, by the way.

Lindsay:

Yes, I know, but this is where politics and science intersect and to say it's absolutely essential.

Zierler:

Absolutely.

Lindsay:

So the truth of the matter is, if everybody that was outdoors and likely to interact with another human wore a mask, we would kill this pandemic. It's trivially true. It's become an act of muscular machismo on the part of the President and some of those around him to set a bad example. And it's tragic because people are going to die.

And so to me, it is a real tragedy that the credibility of science has become a political plaything because many Americans will die because of this.

So, for example, this rally that's going to be held in Tulsa is going to result in no end of tragedies. And yet there is this story that came out today. I mean, I've read the research literature on masks, so, you know, I'm technically up to date. But there was a beautiful illustration of it today of a Great Cuts [Hairdresser] in Missouri where the two hair cutters both had virulent COVID. They turned up to work, although they were sick, but Great Cuts insisted that they wore masks. So even although they cut the hair, between them, of something like 500 people during the period in which they were infectious, there wasn't one infection because their employer made them wear just cloth masks that caught the droplets and prevented the virus becoming an aerosol. So, you know, if things like that were widely known, and if there wasn't this, "I hate experts, you know, I'm going to do the opposite" reaction, which is exemplified by the current President, we actually could kill this pandemic. Very, very, very frustrating. And I felt the same way about the loss of the medical developments we've worked on that actually the simplest, best thing for American health care would be universal coverage and cost controls through something like universal Medicaid. And in some ways, we're wasting everybody's money developing these sophisticated tools without those preliminaries being taken care of.

Zierler:

That's interesting.

Lindsay:

But I'm ever hopeful, and my main reason, apart from my beloved family, for staying alive through November, is to vote for things to change.

Zierler:

And you should emphasize you're a citizen. So you're going to be right there at the poll.

Lindsay:

Of course. Yes, my wife and I have been very, very active. It's rather funny, as Young Conservatives, the day we got citizenship, we started working for the Democrats, which in Arizona was at the time regarded as a lost cause (although no longer I have to say that).

Zierler:

That's right. That's right. Well, Stuart, now that we've made it to the, you know, the present day of the narrative, I want to ask for the last portion of our talk, some sort of broadly retrospective questions about your career. And then a few, sort of, forward thinking questions. So one, in terms of your career in biophysics, I mean, it's a remarkable narrative up to that point, but, of course, what you're professionally known for came relatively late in your professional life. You know, many people, they decided, you know, as an undergraduate, this is what they wanted to do, and yet, for you, in your professional life, you really only fully established your academic identity after you arrived on the scene, which is a pretty unique thing. So my first question there is, what do you think accounts for that in terms of your background, where you came from, your interests? Not staying on the straight and narrow and sort of single mindedly pursuing something; what do you think accounts for that?

Lindsay:

So a couple of things. First of all, my advisor died right at the time I got my PhD. So I didn't have an academic mentor. If you knew the degree of my naivete, you'd be astounded. The second thing was, a completely, I think, laissez faire attitude to life. I just felt that whatever I did would be fun and interesting. I was never bored in my entire existence, always something captivating. And so I think it was just that I didn't feel I needed to make a choice or needed to be driven. Now, when I was hired at ASU, I had a good publication record and good recommendations. But you're right, I didn't have a direction.

Zierler:

Now, in terms of your career in biophysics, what are some of the major through lines of all of the endeavors you've been involved in? What are some of the major research questions or matters of personal curiosity or motivation to make a difference in some way? What do you see as some of the through lines that connect all of the different projects that you've been involved in?

Lindsay:

Well, this is rather a trivial answer, but one is: If I can measure it and do a better measurement than has been done before, right? So, I mean, I'm primarily an experimentalist. And so it's always been a question of in the face of what appears to be overwhelming complexity. What's the thing in this system that you could maybe get a reproducible measurement out of and then learn something about the system? So for me, it's always been astounding. You can read all the theoretical papers you like. You don't make one inch of advancement until you see that data on your computer. And this goes back to the Bohr model of the hydrogen atom. If the numbers don't fit, the theory ain't right.

Zierler:

Right.

Lindsay:

And so it's always being can, you know, can I measure something with some degree of precision? So that's been for me, the common motivator. And, you know, when one asks about big open theoretical questions in biophysics, I think we don't know enough to really know what they are. Now, I do have one right now, which is based on our work on protein conductivity. One of the reasons that I got into this, in addition to having had measurements in the lab I didn't understand, was a wonderful paper by a Hungarian condensed matter theorist that more than suggested, actually, did electronic structure calculations, that proteins have evolved into this rather special state called a quantum critical state. And this is a state that lies absolutely on the boundary between conducting in the Andersen sense of the conductor and insulating and the Anderson localization sense.

And it was reading that paper that made me think, well, OK. I mean, this is actually a good illustration of this point. If this is true, then proteins should have some unusual electronic structure, step one. Step two was: if this is true, it must have been driven by evolution. If it was driven by evolution, function and conductivity must be related. And, you know, you can imagine to build an enzyme and wire it into a chip wasn't an overnight project, but it was driven by that argument that we will test to see if there's a relationship between function and electrical conductivity, and indeed there is. But it's still exotic there's something like quantum criticality, and I have no idea whether it's really important or not. But exotic as it is, it's still led to a question. Well, okay. Here are some possible consequences, can I make a measurement? So that's been the driving force.

Zierler:

Now, I think the next question is particularly amenable, given your career trajectory and your classical education in physics before essentially teaching yourself fundamental issues in chemistry and biology. You know, essentially MIT career, and that is in biophysics. What are some of the most fundamental laws in physics or concepts in physics, not just that are important on a large scale, but that are with you on a daily basis, that you rely on to help you understand any given issues that you're working with on a particular day?

Lindsay:

So, I mean, it's statistical mechanics all the way. There is no life at zero degrees Kelvin, period. And so, of course, physics applies at every level. But the interesting phenomena all come about because of the selection of rare but very important states, through fluctuations in small systems. That's one thing. The second thing I think there's this worth saying is the scope of our ignorance is absolutely amazing. So my favorite biologist (who actually a physicist, stroke computer scientist who's actually head of a biology department now) is Mike Levin at Tufts University. And Mike's whole thing is electrical forces in the development of organisms in biology. And when you see his work, you realize that all the pooh poohing by physicists of electricity and biology, you know, "Oh, it can't possibly be important, Debye screening length keeps out all the field, blah, blah, blah". You know, "Magnetism and bone healing nonsense, there's nothing magnetic in a bone".

Well, actually, the effects of electrical and magnetic forces on the body's organization of various organisms is just phenomenal and intriguing. And Mike's one of the people who's pulling this to pieces at the most basic level. I hope he lives for long enough to get his well-deserved Nobel Prize. But my point is that the horizons are so vast that, you know, a topic that would be regarded as cuckoo is actually not. And I will also say I've gone from being cynical about a long-range role for quantum mechanics and biology to having an open mind now. And I think our whole picture of coherence in complex systems is not as sophisticated as it needs to be to understand biology. So, you know, if I was a betting man, I would put something on long range quantum phenomena in biology at some point, many lifetimes hence.

Zierler:

That's now on the issue of, you know, your recognition of how little we know. I'll share with you just to get your reaction from it to see if you think it applies in your world. The other day I talked to Charlie Baltay at Yale. Charlie is in his 80s now, he spent his whole career in particle physics. And he's now and I just love this about physicists, the general. They never retire, right? There's always been new to work, you know. And he's in cosmology now and he's deep in cosmology and he's working with NASA.

And he said, you know, for my whole career, not to belittle the importance of particle physics, but we were struggling to learn about particles that make up maybe one or two percent of the universe.

Lindsay:

Right. Isn't that amazing?

Zierler:

And now that I'm into cosmology and I'm really writing about dark, dark matter and dark energy, that's the other 97, 98 percent. And why do we say it's dark? Because we don't know anything about it. The only thing we know is that we know it's there. Right?

Lindsay:

Right.

Zierler:

Do you think that that's an apt analogy on the nano scale in terms of roughly understanding the proportion, the proportionality of, you know, in terms of your own career and understanding? That you have a pretty good idea of only a tiny, tiny percentage of what's truly out there to understand?

Lindsay:

Well, I mean, one reason the single molecule biophysics rears its ugly head is we work with very artificial single molecule systems. And in those, I think there's been a tremendous advance in understanding. And I would even say in the theoretical understanding of things like enzyme catalysis there is beginning to be a good model. In fact, Arieh Warshel at USC, a guy who won the Nobel Prize recently, he was arguing what I think is the correct mechanism 20 years ago. But when you get to the collective behavior of these systems inside a cell, for example, or the behavior of many cells in forming an organism, that's exactly right. I think we know that just the tiniest fraction of what we want to know.

So this brings me to another point, which is, you know, he goes back to your question about what's the benefit of DNA sequencing. I think the answer is we will not know until all of the available clinical data and all of the available sequence data is fed to a machine learning algorithm, because I am no longer of the opinion that it's easy to have deep insights into complex systems. And I believe actually I'm not scared of machine learning. To me, I learned F=ma by constant repetition in class.

And so I'm no different from a computer with the appropriate deep learning network. And so I think that the real advances are going to come from enormous volumes of correlational data. And so eventually what's going to happen is genomic features that signal particular disease propensities will emerge from this vast combination of clinical data and genetic data. And then it'll be translated into a simple, actionable item by a doctor.

Now, that means that as far as trying to understand this goes, we've completely bypassed it. Right. But I also think that's a good philosophical question, because if you can manipulate it and use it, this is Feynman's thing: "I have to build it to understand it". Well, if you build it, does that mean you understand it? And I think the answer might just be yes. It becomes a, you know, an issue that's not terribly important. If you can use the tools predictably.

Zierler:

Fascinating. Maybe this is to ask you to put back your politicians’ hat on it. If given the opportunity, or at least here, you know, the hat you wear when you're proposing to grants to the NIH. The things that you're talking about in terms of what we need for the future, right? This is obviously going to require significant amount of support from society at large, right? So what is the top line argument for why society needs to support nanoscale bio physics? What are the big things that when you know, politicians, people that are holding the purse strings, when they say what good does this research hold for society at large? What do you see as the long-term promise of nanoscale biophysics?

Lindsay:

Several, several areas. So with understanding of molecular systems, which are usually the end point targeted by drugs, which, by the way, I think is probably overly simplistic. When you look at the work of someone like Mike Levin, which is much more holistic, I think you'll find completely new areas of drug development.

But nonetheless, with the current process of drug development targets, single ligand molecule interactions and better understanding of that has come from single molecule biophysics already in many cases. But there's a there's a broader thing, which is that in understanding some of these, in my case, new electronic phenomena, I now see a way to this famous Moore's Law problem, a solution of it. And it's this: if in fact protonatious materials, and why has yet to be understood, but if, in fact, they make these fabulous electronic conductors and of course, sensors, they have the property that they, A, self-assemble, and, B, that, thanks to the wonder of recombinant engineering, you can put an atom wherever you want to (which is more than can be said for a solid state nanostructures). So one of the eye-opening things for me is I worked on nanopores, solid-state nanopores for many years and eventually I gave up because I realized you cannot do predictable chemistry on the edge of something that's, you know, so few nanometers in diameter. It just doesn't work. But on the other hand, if you take a protein membrane protein pore, you end up like Oxford Nanopores, selling DNA sequencers. And so the point is biology has solved the problem of regulating atomic scale construction. If you now throw into that equation the fact that I do believe there are fabulous electronic possibilities in biomolecules, I think you've got the answer to Moore's Law. This will not be necessarily be faster laptop chips, but it'll be a new kind of electronics that involves a direct coupling to chemistry. And I can see that happening.

Zierler:

And again, to get back to the societal benefit that even a politician can understand, what is it?

Lindsay:

I probably put it too...... one can argue about what a benefit may be. You can ask the question but, you know, scientists are loathe to answer because they don't know the future. What I do know is that when you develop a new technology and have a bunch of smart people working on it, you have an immediate impact on the labor force and business. And so to put this in terms of today's unfortunately confrontational politics, the United States will only keep an edge in business if it can compete in technology. And if it's not on the cutting edge in not just nano science, but other fields, nanoscience, pharmaceuticals and so on, you know, our economy will decay to be that of a third world economy.

And I think that's probably the primary argument because, you know, whatever the societal benefits, a reason why economic output, why forming a successful company, is useful is because the metric of success is: "Is someone prepared to pay for it?" even if that's a government trying to eradicate a pandemic. It's still a metric. And so it's very hard to predict what the winners will be. But it's certainly true that every new technology generates new economic activity. And if we're not continually doing that, then we're an economically dead society.

Zierler:

Now, my last question focused on, you know, the frontier, what's not known. Over the course of your career? What are some things that you feel personally or as a representative of your field are really, you know, you have a good handle on now that are truly understood but weren't 20 or 30 years ago?

Lindsay:

So, I mean, I would say the primary thing is the role of fluctuations. When I started, I remember virulent arguments at a small meeting held by the Office of Naval Research where myself and my solid-state colleagues were arguing about phonons in biological molecules. And Bob Austin at Princeton would say absolutely not. He said, you've got the time scales all wrong. It's microseconds and milliseconds, not nanoseconds. And the reason, of course, is that biochemistry proceeds like reaction theory. The system fluctuates like crazy until a transition state is found and then it makes a transition. So this means you need reaction theory and you need a good descriptive description of the fluctuations in the system, and you finally get a handle on it. It turns out that the end timescales are actually very long. So that is a picture that has emerged clearly over the span of my career. A second picture that has emerged is when I started out, enzymology was "lock and key". So somehow, you know, a substrate binds an enzyme and something happens to reach a transition state, a structural transition state. And then the end state of the reactance comes about. What Arieh Warshel showed many years ago (that now I think is widely accepted) is that it's an electronic process. The dipoles surrounding the catalytic site fluctuate randomly until they drive the electric state of the substrate to the transition state. And then it will dissociate into products.. And actually there is a huge thing here: ever since I first read the word enzyme, you know, I at least had some quantum mechanics as an undergraduate, and my question was, what about Fermi's golden rule? Reactants and products don't have the same electronic states. How can the electrons possibly do anything? And the answer is you have to satisfy Fermi's golden rule. And so all of these things are actually driven by electronics and you need degenerate states between reactants and products. So that's been a big learning thing for me.

Zierler:

Well, Stuart, my last question I want to ask, as I mentioned, I sort of forward-thinking question. And that is, what is left for you personally? What are the things in your field that most motivate you to remain active, to be on top of all of the research? And what are you most personally interested in accomplishing for the rest of your career?

Lindsay:

Well, I really want to see this new technology based on protein conductivity succeed. I would love to be around for long enough to understand it at a fundamental level. I wrote a small review recently identifying what I think precisely the theoretical problem is. I don't know how to solve it. I think it may, in fact, be related to this proposal of quantum criticality in protein structure. But there's such a vast gap between such an idea and what we know of protein electronics that I don't know how to fill it right now. So I have a number of collaborations with theorists and I'd like to see that come to fruition. I do believe that they are a great potential technology for pathogen detectors. I believe you could have a chip, by the way, that would be a universal omics platform. It would tell you everything from a spot of serum from a patient. It would tell you everything that half a dozen just different diagnostic instruments would now. And I believe this DEMP technology that we've been working on has that potential. So I would very much like to see at least some of that come about.

Zierler:

And in terms of pushing those advances where you looked at the various components for how those advances come about, hard work, luck, funding, technology, right? What are the most important components for it for achieving these advances? Look at looking to the future.

Lindsay:

Number one is having a motivated team. Of course, you need funding. My friend John Spence (who's someone you should interview, by the way) used to have a quote on his door, which was that "Chance favors the well-funded mind". [Both laugh]

So, of course, one needs funding. And I'm extraordinary lucky. I mean, one reason I haven't given up is over the years we've built up a repertoire of tools. We're now moving into nano fabrication. So we are establishing quite a good chip processing lab in addition to using fabrication facilities around the country. So, you know, having access to those things is important. I think what I will say is that perhaps the most important thing that research universities could do would be to move away from the single investigator, "my lab is my empire", model to a model of both collaboration and shared resources. So in that way, even a university with fairly modest research funding could afford to buy collaborative research tools that were then funded for a group of investigators. So one thing we've done with every tool my center has acquired, we've made it available as a general university facility. We have a small recharge that supports the tech who takes care of the equipment and so on. And that's the way my labs have operated for many years, and it's the way ideally all universities should operate. But they get into these silly battles to hire people who think that the more hardware they have, the more important they are.

Zierler:

I wonder in terms of the pandemic and the fact that we're all zooming all the time now, I wonder in some way, ironically, if that's going to foster this kind of collaboration that you're hoping for.

Lindsay:

You know, just maybe, just maybe.

Zierler:

Stuart, it's been phenomenal talking for me. Thank you so much for your time.

Lindsay:

Well, thank you, David. I enjoyed it. It was a break. I've actually been working on trying to crack a lab problem, and my brain has been hurting. So that's an interesting distraction.

Zierler:

Glad to be of service.

[End]