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Credit: Stanford Photonics Research Center
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Interview of Steven Block by David Zierler on June 9, 2020,
Niels Bohr Library & Archives, American Institute of Physics,
College Park, MD USA,
For multiple citations, "AIP" is the preferred abbreviation for the location.
In this interview, David Zierler, Oral Historian for AIP, interviews Steven Block, W. Ascherman Professor of Sciences, Stanford University. Block describes his German-Jewish heritage on his mother’s side, and his father’s Eastern European Jewish heritage. He describes growing up the son of a physicist and the importance of skiing and music in his family and spending his early childhood in Italy while his father was a visiting scholar. Block describes the rest of his childhood in North Carolina, and then Illinois, where his father worked for Duke and Northwestern, respectively. He explains his unique interests in Chinese and oceanography and why this led him to the University of Washington in Seattle, and he describes his subsequent pursuit of physics and ultimately biophysics at Oxford University. Block discusses the formative relationship he built with Max Delbruck at Cold Spring Harbor Labs where he worked on phycomyces, and he explains his decision to go to Caltech for graduate school to work with Howard Berg. He describes his postgraduate interests in sensory transduction in e. coli as a postdoctoral researcher at Stanford, and he provides a history on the discovery of kinesin and why this was key for his research. Block explains his decision to join the Rowland Institute and he discusses its unique history and the freedom it allowed its researchers, and he describes the opportunity that allowed him to secure tenure at Princeton. He describes some of the difficulties in convincing his colleagues to consider biophysics as “real” physics and the considerations that led to him joining the faculty at Stanford. Block describes the difficulties he has experienced when his laboratory site was displaced, and how, in dark way, he was prepared for the pandemic lockdown before most of his colleagues. At the end of the interview, Block reflects on his contributions, he explains the central importance of statistical mechanics to biophysics, he explains how he has tried to emulate his mentors in the care and interest he has shown his own students, and he prognosticates on the future of single molecule biophysics.
Okay. This is David Zierler, oral historian for the American Institute of Physics. It is June 9th, 2020. It is my great pleasure to be here with Professor Steven Block. Steven, thank you so much for being with me today.
It is my pleasure as well.
Okay. So, to start, please tell me your title and institutional affiliation.
Alright. I suppose my full title would be the Stanford W. Ascherman Professor of Sciences, at Stanford University. I hold appointments jointly in biology and applied physics. I am a biophysicist.
And not to put you on the spot if you don't know, but can you tell me a little bit about Ascherman?
I actually, ironically, don't know much about him at all. He was a doctor, a medical doctor, who was educated at Stanford University and to the best of my knowledge left in his will a provision for two endowed chairs at Stanford. There's an Ascherman professor in the medical school, and there's another one in the department- oh, sorry, the School of Humanities and Sciences. And so, I hold the chair in Humanities and Sciences. It's one of a large number of endowed chairs, of course, that Stanford metes out to their faculty, presumably as rewards for certain things. Stanford, unlike a lot of universities, does not endow their endowed chairs with a large and healthy allowance which can be spent on various things like a postdoc or a graduate student, or even on lavish parties. In fact, we get a total allowance, I believe, of $5000 a year and no more, which scarcely pays for the beer and pizza in my group. And that's it. So, it's just simply an honorific title.
Uh-huh. Well, let's take it right back to the beginning. Tell me about your parents and where they came from.
I was born in the United States in North Carolina, but my mother hails from Germany. She was born in Würzburg, Germany in 1925, and I'm Jewish, Ashkenazi Jewish on both sides of my family, and my mother's family fled Hitler, first to London and then eventually to New York. All the relatives who remained in Germany were exterminated by the Nazis. So, my mother was keenly aware of this. She had to- She played piano and she had to learn how to play the accordion, because one of the ways they got out of Germany was to pose as a band of traveling musicians. My grandmother was a singer, she was an opera singer. She eventually sang in the chorus of the Met in the United States. And she used to give some solo concerts in Germany. So, she was the singer in this fake band.
What was your mom's family's socioeconomic status in Germany?
They were thoroughly assimilated Jews. They were scarcely religious at all. They did, of course, practice Judaism, but like a lot of Jews I know including myself, rarely went to temple except on perhaps Yom Kippur or Rosh Hashanah. And that was it. They considered themselves very German, first and foremost. And so, like many of the academics in intelligentsia and the upper-middle class and the bourgeoisie Jewish in Germany, they considered themselves thoroughly assimilated and it was, so the Nazi era came as quite a shock to them. My grandfather, my mother's father, actually was a glove manufacturer in Würzburg, Germany. He came over to the United States, and unfortunately passed away of a heart attack soon thereafter. They smuggled a lot of the family fortune out into the United States. And there's an amazing story behind that, which is my grandfather would take a train into Switzerland through Basil, and if you've ever been to the Basil train station, you know that there's a long stretch of the track, and there's a Basil station that's on the German side and the Basil station on the Swiss side separated by a few hundred yards of track. And what would happen is they would let the passengers off on the German side, they'd go through security, and come out on the Swiss side. They often would be searched. So, to prevent being searched, he would take a satchel of money and shove it in the accordion pleats that were between the cars. In the German trains. And sometimes they would use the same train and simply advance it down the rail, sometimes they would swap out trains. So, he didn't dare send all the money at once. He would have a code word when he got to the other side. He would phone the family, which at this point was in England, saying something like, "The weather was good." to indicate that the money had made it through. And he did this on a number of trips. And at some point, and I'm unclear on the details of this, I don't think it was during one of these passages, but at some point, he was rounded up by the Nazis, and he was thrown into Dachau. Which is near Munich. And amazingly enough, in this, he actually managed to escape from Dachau with the help of an SS officer who recognized him. This was an officer whose life, apparently, he'd helped to save in World War I. My grandfather had gotten the Iron Cross fighting for the German side in the First World War. And it was later to be his ticket out of Germany. He had to get forged papers indicating that he'd never been arrested and eventually was able to pass through the borders and join the rest of the family in London. And then eventually they came to New York City.
Woah (laughter). That's amazing.
So, this is the stuff of which movies get made.
And this is a story that got passed down through my mother. She was, however, extremely reluctant to talk about what happened in Germany for many, many years. And my mother passed away just a couple of years ago, so we may never know those stories.
Right. But what you do know, you got from your mom?
I did. That's right. Also, my grandmother, Erma, who was the opera singer. And she apparently had quite a bohemian youth. She and her husband had a motorcycle with a sidecar, and she'd go cruising around Germany in the sidecar. So, I guess that was active. My mother's side of the family is very musical, and so my interests in music, I think, come from that side. My father's side, on the other hand, is also Ashkenazi Jewish, but came to the United States much, much earlier. Probably around the turn of the nineteenth Century. Although the details of that are not well-known to me, or to him for that matter. They settled in New York, eventually in Newark, and in fact it was in Newark where my mother and my father met each other. They attended the same high school. Weequahic High School. It's the same high school that Phillip Roth went to, by the way.
I was going to ask, yeah (laughter).
And interestingly enough, they actually didn't meet in high school, even though they were in the same class. They met later on when my father was at Columbia. But my father's family is from the shtetls, from the small towns in a place that used to be called Galicia.
In the settlement, which is today part of Ukraine. And I can tell you that the German Jews looked down on the Galitzianers.
Of course, right.
The German Jews were bourgeoisie, they were elite, they were assimilated. The Galitzianers were poor folk from the sticks. And my grandmother was not too thrilled that my mother was going out with my father when she found out about this. My grandmother has an interesting story. She was divorced, which was very unusual in her age. The first person she married, a guy named George Block who was my father's father, served in the 10th Mountain Division, in the U.S. ski troops in World War II. Trained at Camp Hale in Colorado. And eventually helped build the road up Mount Mansfield in New Hampshire and was a ski bum. In fact, he was such a ski bum that he eventually divorced my grandmother to go off and pursue his interests. Which is why skiing is such a big thing in my family. Both my mother and father were skiers. They founded the Newark Ski Club shortly after World War II. And eventually bought a house in Aspen, Colorado, where they lived for practically forty, fifty years, and started me skiing when I was three years old. I went to first and second grade in Italy, and part of that was in Cortina, Switzerland- sorry, Cortina d'Ampezzo, Italy, in the Dolomites, where I learned to ski and at the age of about five or six and got really good at it. I won my first ski race when I was six years old (laughter). I may have been the only racer in my category, however (laughter). So, my father's family, as I was saying, my grandmother was extremely bright, but she never went to, never finished high school, but she was one of these people who could execute the New York Times crossword puzzle in a matter of ten minutes or less. She had two brothers who both went on to become lawyers. And, as I was saying, she divorced her first husband, who was my grandfather, and she married a Catholic, which is in that day was outrageous. And he was a winder washer, but he eventually got contracts for washing windows of places like the Empire State Building. So, they did very well. And she spent the last part of her life cruising the world like some sort of reborn Auntie Mame, collecting very loud jewelry in the jewelry shops of Europe and so forth. She loved to travel, and she was a larger-than-life person. She was very, very vocal and outrageous in a lot of ways. So, on her side of the family, she had two sons, my father Martin, and my uncle Robert. Both of them went on to become physicists. My father became a particle physicist, first trained in Columbia, and my uncle became basically a nuclear reactor physicist. And he is a dean at Rensselaer Polytechnic Institute today. My father was at Columbia, he later went to Northwestern University. But by way of Duke. So, his first assistant professor job was at Duke University. He was there for a number of years. I was born in Duke University Hospital. And eventually, as I said, the family settled in Evanston, Illinois at Northwestern. But my father was busy collecting his money so he could buy his place in Aspen. He bought a house in Aspen back when you could buy a house in the tony west end for on the order of $40,000.
That was back when most of the houses were dilapidated and falling down. They were old Victorians which hadn't been kept up. The roads were dirt, not paved, and it was a very different place. So, as I grew up, I got to see Aspen change enormously. As you know, Aspen is not only home to a music festival in the summers, but also to the Aspen Center for Physics, which is very active in the physics world.
And my father was there, virtually at its founding in the mid-1960s. It had been only in existence for of order eighteen months to two years at the time he joined. Later on in, I think it was approximately 1985, my father was responsible for establishing the winter conferences at the Aspen Center for Physics.
Of course, because that's when you have to ski. You have to do it in the winter.
That's right! That's right. So of course, they've had a very active program in the summer for many, many years, and they were reluctant to start a winter program, largely because in high season, the hotels are very expensive, and they thought that the physicists couldn't afford it. My father had noticed at the time that there was actually a low point in the middle of January because families with children would come out and ski over the Christmas holidays. And people who were free to come whenever they wanted, the younger, the independent, and the wealthy, would come out in February and March when the snows were at their best. So that meant that the second half of January was generally a low point, even though it was high season. So, he was able to arrange for hotels during that period at bargain rates, and this proved to be highly successful. And they started with first one winter physics conference in particle physics, his field. But that quickly blossomed. And today, there are as many as eight or nine conferences every winter, and there's no longer a low point in high season. They arrange for hotels throughout the entirety of the season. And somehow the physicists are able to afford it.
Do you know who your father's advisor was at Columbia?
He, he was I.I. Rabi.
And, or one of his professors, and the other professor, oh gosh, I'd have to look up his name and get it to you. The other, he was directly under someone else, not Rabi. He considered Rabi to be his mentor in many ways, but his actual professor was someone he didn't get on with and was never mentioned. So, I'll find the name for you and we'll add it to the transcript.
Now as a matter of both his scientific style and parental style, did you grow up in a world of physics? In other words, did he involve you in his professional world?
I grew up in a world of physics, no question about it. It's ironic, and we'll get to this in a bit, but I came to be a biophysicist by revolting.
Against my physics background. Which is kind of ironic, of course, because today, I certainly consider myself to be a physicist in many ways, and I have come to run one of these winter physics conferences of which we spoke. In fact, it's the longest-running single physics conference in the winter conferences. The Single Molecule Biophysics Conference, which was started in I guess 2001, and here we are in 2020, and it's still going. But I grew up with physicists all around me. My parents were rather social, and my mother was an excellent cook, and so my father was fond of bringing physicists home for the evening, and wherever we went, and we went a lot of places. So, I've lived almost everywhere in the world there's a particle accelerator. Except for Dubna, Russia. So, I spent a lot of my youth in Geneva, in Switzerland, because my father spent more than ten years at CERN. I've spent time in Evanston, Illinois, which is near, it used to be near, Argonne. And is also near Fermilab when Fermilab got built. I've spent time as a small child out at Brookhaven at the bevatron, which was one of the first accelerators. And sorry, out at Berkeley at the bevatron, and also Brookhaven on Long Island. So, Brookhaven, Berkeley, CERN, Argonne, NFNAL, all figure in my youth.
I wonder if you've ever compared notes with Persis Drell, for who was perhaps even more drenched in physics growing up?
Oh, I know Persis, yeah. I met Persis. I was invited to give the Bethe lectures at Cornell. Deeply flattered, in fact, to have been invited to do this, because it was relatively early in my career. And I think this was sometime around- maybe it was in the late nineties, early 2000, and I met Persis Drell there. I also got to meet Hans Bethe before he died, which was a thrill for me. And yeah, so I also know Persis in another way, which is that her father, Sid Drell, of course, was deputy director of SLAC for many years. Sid Drell was in a group called JASON. I guess we'll get to this, and so I actually knew Sid better than Persis, and I knew him through my summers at JASON. So, we've had a chance to compare notes. I grew up with physicists all around me. I met Richard Feynman, for example, when I was young. I met Georges Charpak, who was a Nobel laureate. In fact, Georges Charpak and his family loved to ski, and so did mine, and we would sometimes join them on ski vacations. It was Georges Charpak who took me down the Vallée Blanche at Chamonix. Back when I was, I think, a teenager. So, I have all kinds of childhood memories of famous physicists I have known.
So, where did you, growing up, I mean you were all over the place. Where did you spend your formative years, in terms of coming of age?
So I, although I was born at Duke University in North Carolina, my parents left relatively soon, so I didn't pick up much of a southern accent. In fact, my accent insofar as I have one is tinges of New York. I will say words like "ah-range" instead of "orange," "far-est" instead of "forest." I will say, "Mary" for the girl's name, but "merry" when you're happy. Not mary/merry. So, I have tinges of New York, which is ironic because of course, I've never lived in New York my entire life. However, I did live in the north of Italy. My father went on, I believe it was sponsored by the Guggenheim Foundation, went on a Guggenheim fellowship to Italy when I was four, five, six years old. And to work with a physicist named Gianni Puppi in Bologna, University of Bologna. And I think he quickly grew bored with what was going on in Bologna, and so he decamped the whole family and moved them to Cortina d'Ampezzo up in the Dolomites. And so, they sent me to school there. And there's some interesting stories with that as well, so Cortina had been the site of the 1956 winter Olympics, as you probably know, and so in that winter Olympics, there was an Austrian from very nearby. In fact, a lot of the people in the Dolomites speak German rather than Italian, as their first language. And so, an Austrian from a nearby valley named Toni Sailer had won three gold medals. And this inspired the folks in Cortina that they could grow an entire generation of famous skiing athletes, because of course they had the slopes and it was a winter destination resort. And at that point it was becoming very popular with the jet set. So, what they did is, they transformed their educational program. The kids would go to school in the morning until about noon, and then school would break, and we'd all go off to ski school in the afternoon. And it was just wonderful (laughter). So, I had a winter's worth of ski training at the age of five thanks to this educational system. The other weird aspect of this was that as you know, there's really no separation of church and state in Italy. And of course, it's run by the Catholics. So several times a week, the local priest would come into our school to teach us our catechisms, and he would hand out things that for all the world looked like baseball cards, except they'd have a picture of Jesus on the front performing a miracle, perhaps the loaves and the fishes, or walking on the Sea of Galilee. And on the back were all these empty little hearts. And the idea was that every time you said a prayer, our father, hail Mary, or did a good dead, you could take your color pencil set, and you could color in one of the hearts. And these were then collected by the priest at the end of the week. Well, my parents had given me this fabulous color pencil set, from Caran d'Ache. This was the famous Swiss color pencil manufacturer. And they were to little Italian kids what the Crayola crayons are to American children. You know, you get this enormous box of many colors. But there was no opportunity in the classes I was taking to use all these colors. So, I would use them to color in the hearts on the back of the cards. I would color them with rainbows and stripes and paisley and dots, and I used every color in the set. And of course, I handed in the cards every week fully endorsed. This was-
Now, were your parent’s secular, so secular that they weren't bothered by this? Or were they just Jewish enough where they were horrified by this?
They weren't bothered at all by this. And so, the story continues, as you'll see. So, none of the other kids, of course, would dare do this, because they would spend God knows how many years in purgatory for each incorrectly colored part. My mother would go shopping every day, as you would do in Italy, and she would go to the local trattoria or the salumeria or the- and, to pick up our food. And one day she runs into the local priest, who comes up to her and says, essentially, "Your son is bound for the priesthood. He's handed in all these wonderful cards. Every time I call him in for the catechisms, he absolutely knows the answer. He's memorized all these passages. He's extraordinary." And my mother starts laughing and says, "Oh no, no. You don't understand. We're Jewish and he's a smart aleck. He just knows these things. And so, he knows lots of other things as well, it has nothing to do with Catholicism. And as for the colored circles, he's just using up his colored pencil set." So instead of- she was hoping to inform the priest about this perfidy on my part, but in fact, the priest shook his head and just couldn't believe it. He decided I had to be all the more holy to be growing up in a background of devils like this, and that this was somehow a transformation on my part. And so, my mother went away shaking her head. So, she tried to explain it to him, but I don't think it worked. So, I came back from Italy well-schooled in Catholicism. My mother had another fight with the instructor because I'm left-handed, and they wanted to train me to write right-handed. Back in those days, you literally dipped your pen in an inkwell. And she succeeded in that. She got the local instructor to agree to teach me left-handed, but they had to teach me to use a blotter under my hand as I moved, because I would have to blot the ink as it passed underneath my left hand, writing from the left to right. So, I learned to write with a blotter. I learned a lot. In first grade in Italy, you not only learned your addition and subtraction, but you also learned multiplication and long division. So, I came back to the United States to Durham, North Carolina, having schooled in Italy-
And the classes were in Italian or English?
Oh, this was Italian public school. Everything was in Italian. So, I was thrown in the deep end of the pool to learn Italian. So, I learned how to read and write in Italian before English. I learned to speak Italian. I still speak Italian to some extent, but with the vocabulary of a five-year-old (laughter). And I haven't spoken it for many years, and so fast forward to the days of my honeymoon, which was in 1986, I believe. We went to Italy and the language came flooding back. It was amazing. I could scarcely speak it, but I could understand everything that was being said to me. And of course, the Italians are very generous if you even attempt to speak the language. They will go out of their way to help you. In contrast to the Swiss and the French, by the way, when speaking French, who will do nothing of the kind. But I learned to speak French and I still do to this day, by going to public school in Switzerland, but we're getting ahead of ourselves. Anyway, back to the Italian story. Came back to North Carolina, and the school there wanted to put me back into first grade, even though I should have been in second grade at that point, on the grounds that I couldn't read or write English. Which was absolutely true. Italian, of course, is phonetic, so I would pick up an English text and I would start reading it as if it were phonetic Italian. That was pretty outrageous. So, my mother had a big fight with the school board and eventually they moved me up into the appropriate grade. So that was the time in Italy. That I had a fabulous time learning to ski, and got very good at that, and to this day, I'm still an avid skier.
So, when did you move back to North Carolina?
So, we moved back to North Carolina, this would have been about 1960 or thereabouts. And you know, we were in Italy in '59 and '60, maybe it was '61.
And your father was on the faculty at Duke?
He was on the faculty at Duke in the physics department, that's right. So, my father's contributions to particle physics were several-fold. He also had an interesting story. He was an experimentalist. And was interested in elementary particles. And back in the 1950s, lots of particles were being discovered left and right. This was before Murray Gell-Mann's eightfold way and the understanding of quarks. And so there seemed to be a particle every month or so that was being discovered, and my father was one of the co-discoverers of the eta meson, which has a three-pi resonance. He's also the inventor of the helium bubble chamber. The hydrogen bubble chamber had been invented by Glaser and others and was used very successfully as a particle detector in that period, and the helium bubble chamber offered essentially alpha particles as targets. Because those were helium nuclei. And so, he built a helium bubble chamber. This turned out to be a huge experimental challenge, because of course as you cool helium, it becomes superfluid, and it's very hard to contain. So, the challenge of building a helium bubble chamber was to be able to get seals that were sufficiently tight, that you could expand and contract the helium to produce the bubbles, and yet not have it leak completely out of the chamber. So, a lot of work was- he eventually used indium metal as a seal, which is still used to this day [inaudible 26:08] with indium. But all that was just being worked out at the time. So, he invented the helium bubble chamber, started some work with this, and largely on the strength of that, I think Northwestern recruited him from Duke. And so, for my high school years, we moved to Northwestern University, where my father continued to work on the helium bubble chamber at both Argonne and then eventually at Fermilab.
So, your teenage years were in Evanston?
They were. It was a time of great tumult. Much as today. It's ironic as we're speaking now, there's the funeral of George Floyd taking place on TV. I was watching it earlier. When I was there, it was the Vietnam War. I was very active and marched against the war in high school.
You were too young for the draft, though.
Yes and no. So, I was too young for the draft in high school. But when I graduated high school, back then they had a number drawing based on your birthday, and there was a lottery, and they would draw the birthdays from a hat. My birthday is October 4th, and that was, if I recall correctly, number 66 in the draft. That's a very high number, or low number I should say. And giving me a very high probability of being drafted. I didn't want to go to Vietnam, I didn't think Vietnam was right, and I was adamantly opposed to it. So, I eventually wound up moving to Oxford University. I guess we're getting ahead of ourselves here, but I moved off to Oxford partly to avoid the draft. At the time, student deferments existed, but the rumor was that Nixon was going to get rid of the student deferment. So, one of two things was going to happen. Either we were going to get out of Vietnam, or the war would continue, and the student deferment would be about abolished, and I would be drafted. So, against that eventuality is one of the reasons why I went in fact to Oxford. There are other reasons as well. We'll probably get to those. But I was active against the war, and in fact, I spent one year before Oxford at University of Washington in Seattle. And during that time, I was actually arrested during a demonstration. Thrown into jail for the first time in my life on a trumped-up charge, allegedly for throwing a rock at a police car, which missed. There were members of the Seattle Tac Squad interspersed in plain clothes amongst the demonstrators, and they were rounding up selected demonstrators that they thought were leaders and charging them. And so, I was viewed as a potential leader and I was charged. And on the initial sentence was convicted. I then managed to get a lawyer to help me who worked for the ACLU. On appeal, the charge was overturned. So, I have one arrest on my record for anti-war activities.
Where were you during the convention?
During the '68 convention, I was still in high school. There was the riot of Grant Park, you might remember, and Mayor Richard J. Daley of Chicago who was fond of talking to the press but always had his foot in his mouth, very famously said when he was told, the policemen are creating disorder in the streets, he said, "The policemen are not here to create disorder, they're here to preserve disorder" (laughter).
It's true, you can look it up. But you know, it's ironic, you fast-forward to today, and we see the very same problems with our police. In fact, tomorrow, there is a so-called "shut down for STEM." The United States will, the academic community will shut down for the day and so I'm glad our interview turned out to be today and not tomorrow, because then I'd have to beg off.
That's right. And AIP is taking tomorrow in that regard quite seriously, and I think it's, just editorially, it's a very important thing to do.
I'm glad to hear it. It's terribly important. Our country is long-overdue for serious change. And in some way, it's very heartwarming to see the demonstrations that are happening because they do take me back to the Vietnam era we were talking about. And the demonstrations in the streets, which ultimately had effect, perhaps not as much effect as most of us would have liked, but it did change America and we got out of Vietnam. And it's time for America to change again, and I can't even contemplate what it would be like to have four more years of racism, homophobia, anti-Semitism, xenophobia, under the Trump presidency. So hopefully this will all change come this fall. And there are deeper matters that the United States needs to examine itself about. Ironically, you know, I think we fought the Civil War, but we never quite resolved it, and it's time to put that behind us. The Civil War is still being fought in many quarters in the United States, and an astonishing number of people in the United States still support these abhorrent racist views. What shocks me is not so much that Trump is president, but that he got elected in the first place. Which means that there has to be a significant level of support for him and his ideas in this country. So, either we live in a confederacy of dunces, or more likely, there are people in the United States that will need to be outvoted and removed. I think it was Wolfgang Pauli who might have said that science advances one funeral at a time?
So, I think in many ways, social progress is like that as well. I think it's true that we make progress one funeral at a time, and a generation needs to be removed and then die off before this country will hopefully come to its senses and put racism and anti-Semitism and these ideas behind them. It's not happening at the speed that any of us would like.
Right. Now, to get back to the parallel in the 1960s, as a high school student were you a standout in math and science?
Well, yes and no. I mean, I graduated high school with something called the Harvard Book Award, which is a, you know, I guess it's the alumni of Harvard give out this award in the hopes that you'll join Harvard. I went to an extraordinary high school, Evanston Township High School at the time was rated as one of the top high schools in the country. They had a grant from the Carnegie Foundation to teach, for example, oriental languages. I studied Chinese for two years. In high school. Which was unheard of at the time. Although today I would say [speaks in Chinese 33:11], which means I forgot it all. But I developed an appreciation for Chinese culture, which I carry to this day. And I was not first in my class by any means, but my graduating class consisted of something like 1500 individuals, which was very large. I was probably in the top ten of those, although I don't actually know. So, I did well, and I certainly did well enough. And most of my colleagues in high school were going off to prestigious east coast universities. They were going to Harvard and Yale and Brown and Stanford and MIT. I was a bit of a rebel because I was active in anti-war movement and at the time, I was very interested in the far East. I was interested in Asian languages; I was interested in Asian culture. And the other thing I was interested in, believe it or not, was the oceans. You know, this is the time when Jacques Cousteau was making all these films, and I wanted to swim with the whales just like Jacques. So, I looked around at colleges and wanted to find one that had an undergraduate degree in oceanography, and also an undergraduate degree in Chinese language. Because those were my two interests at the time. I wasn't interested in physics at all.
And was that part of the rebelliousness in you?
Did your father, I mean, either subtly or not so much, did you feel pressure to sort of go into physics?
So, I'll tell you. So, here's what happened. So, I looked around for all these colleges and universities, and I found one that actually had an undergraduate degree in oceanography and an undergraduate degree in Chinese language. And that was the University of Washington in Seattle. So, I applied for it and got accepted to the University of Washington, and I went off there in my first year. And I went to the college counselor and of course in high school, I had had advanced placement everything. I had advanced placement physics, and chemistry, and biology, and history, and English. And so, by rights, I should have just entered college as a sophomore. But I got some bad advice, and the advice I got from the counselor was, "Oh, we don't really trust those AP courses. They're really not up to our standards. What you should do is you should take all these freshman courses." These were the large freshman classes in physics and biology and chemistry and so forth and so on. And not only that, but you couldn't actually take oceanography courses until you were a sophomore there. So, I got frozen out of the oceanography classes my first year. Now, this turned out to be very bad advice, and I went to classes and I was bored stupid. I did agree to take freshman physics, and this was in response to my father who said something to the effect of, "Well, go ahead and I just want you to take it. You don't have to love it. It'll stand you in good stead down the line." And I was rolling my eyeballs and, "Oh god, okay I'll do it." So, I'd agreed to do this, mostly as a favor to my father. But I was a bit rebellious, and I was doing all sorts of things. In that freshman year, I was so bored with my classes, I would take several days off a week and go and do other things. One of the things I did was I went off to Crystal Mountain, Washington, which is the local ski area. I skied a lot. And I enrolled in a ski teacher training class. And I became a certified ski instructor in my freshman year. I joined the University of Washington Climbing Club, and we climbed up Mount Rainier. This was the year they broke the world snowfall record up at the Paradise Ranger Station. They had something like one hundred feet of snow. And the only way you could get to the ranger station is they put a hole in the roof, and they dug a tunnel down and you'd enter the roof of the ranger station, which was totally under the snow. So, I would go off climbing, I would go off skiing. I took a class in calculus. Again, I'd already had AP calculus and so that was kind of boring. At one point my instructor said, this is jumping ahead, when she heard that I wasn't going to be at the University of Washington the next year, she asked me to take the differential equations final instead of my calculus final. I said, "But I've never had a class in differential equations." She said, "I know, I just want to see how you do on it" (laughter).
So, I did. I still don't know if I passed or not, but it was a learning experience. I actually was able to solve a couple of the differential equations simply by looking at them and taking some guesses. But back to the physics class. I was thrown into this large, you know, 400-person physics class, and it was as boring as all the other classes I took. But there was one thing about it. They gave an exam or quiz in the first week or so. And they target the students who did the best on that quiz to join a kind of honors section. So, I was roped into the honors section. Okay, more work, what the hell. I was so bored. I took the honors section, and it turned out what this consisted of was every weekend, they would take you to the house of a faculty member, this group of perhaps five or ten students, and you'd spend the afternoon just chatting with the professor. And this was a transformative experience for me. I got to go to their homes, they would feed us little snacks, we got to talk about physics. But it was very different from talking about physics when I was at my home. When my father talked about physics, he was talking about it with his colleagues at a level that I couldn't possibly understand. And I was excluded from the conversation. By contrast, here I was being included in the conversation. I was treated with amazing respect. No one had ever treated me with respect before. And no one thought I had any ideas to contribute at all, and so this was an amazing experience for me. I thought this was the best thing since sliced bread. I got to know my professors better, I got interested in several subjects and so forth. And so, I found myself being dragged into physics, ironically, not because my father was a physicist, but rather because I was in this little section. So, then the change happened, and my father went off to CERN at that point for what was to become about ten years of work at the accelerator there. And if you're above a certain level at CERN, a level of Fonctionnaire or above, it turns out that one of the benefits of being on their faculty is that they pay for the tuition, the college tuition, of your sons and daughters. So that's wonderful, that meant my college tuition would be paid for, but there was a catch, and the catch was that you had to go to university in one of the member nations of CERN. Now, the United States was not a member nation of CERN. It was the European Center for Nuclear Research, and so my father wrote a letter to myself and my sister, who at that point was in University of Colorado. She's one year younger than I am. And wrote to us both and said, "Look, if you guys can get accepted into a college in Europe, it'll save us a whole lot of money, and besides, you might have a great experience." So, my sister spent one year at the University of Tuo but she was just a year, and then she came back and finished in Colorado. And I wrote off to British universities out of the blue, something to the effect of, you know, "I'm looking to transfer to Oxford." And I got back a kind of snooty letter, saying, "We do not accept transfer students. Second of all, we only accept students that have taken certain types of exams." And so, on and so forth. And so, I thought, well what the hell? I'll take some of these exams. And also turns out that university in England is only three years rather than four years. So even if I started again as a freshman at Oxford, I would still graduate at exactly the same time that I would at the University of Washington. But of course, I hadn't been accepted at Oxford, and at the time, you had to go through something called UCCA, which was a sort of central clearing house for applications to colleges in England. And so, I sent my application off to UCCA and then it wound up at Oxford. And at this point, I think my father may have intervened, although the details of this are unclear to me. But he, or I think he knew some people at Oxford, but the bottom line is that a couple of months later, I get a letter back saying, "We would accept you at Oxford based on your degrees," I'm sorry, "based on your grades, based on what we know about you, based on your having applied through UCCA." And so, I got accepted. But I always felt awkward about that, because I think in the background, my father may have played a role in getting me in, and the last thing on Earth I wanted to do was advance my own career as a result of my father. In fact, I'd spent my entire youth rebelling against this. And they told me another thing, which was that if I wanted to go to Oxford to "read" a subject, which is the way they talk about it, I would read physics. And I thought about it and I said, ehh. Actually, the only thing that I really got a kick out of in my freshman year at University of Washington, it was the physics class. So, I went off to Oxford to read physics. And I got there, but I hadn't wrapped my head around the full extent to which I was committing myself at that point, because I'd assumed Oxford was just like any other American liberal arts college, in that I could take physics but I could also pursue my other interests on the side. I discovered, to my shock, horror, and dismay when I got to Oxford that if you go there to read physics, physics is the only subject that you take. Even the maths, where they use an "s," even the maths that you take are not taught by the math department, they actually taught by physicists and they teach you the maths that you need specifically for physics. And so, it was kind of a shock. In my first year at Oxford, I spent the year being seriously challenged. I was also challenged because English students receive a really good education in high school. They specialize. The ones that go to Oxford wind up not only taking the famous A-levels in England, but also S-levels, which are a level above that. And so, they come in extremely well-prepared, and they were arguably probably a year or so ahead of me in terms of their physics when I joined. And this would have been in 1971, that I arrived at Oxford.
Steven, culturally, what was the scene like in 1971 there? Had the counterculture reached Oxford at that point?
Yes and no. Britain was then, and probably still is, a very classist society. It was the first time in my life that I really- well, no actually, second time in my life, that I really experienced overt anti-Semitism. A lot of people-
Overt as in, like, really overt?
Well, no. Interestingly enough, with a last name like Block, that's not necessarily Jewish to a lot of the British, and so I'd hear expressions in polite conversation with you know, "He Jewed him out of this," or comments about Jews in general, which would just come up freely in conversation, which I found sort of deeply offensive, but of course, I didn't say anything about it. And so, it was just part of the culture.
I wonder if your Jewish identity strengthened at that time? Just as a reaction to where you were?
Yes and no. So, I had, neither my parents nor I are in the least bit religious. I don't believe in a god. I'm probably more towards the Atheistic end of the spectrum than the Agnostic end of the spectrum. So, I find it completely inconsistent with my training and background and thinking as a scientist. So, I did not become more religiously Jewish as a result of this, but I felt-
I was thinking more, Steven, in terms of Jewish pride, and like, maybe identification with Israel after 1967, that kind of thing.
Yeah. So of course, you know, the Six Day War happened when I was in high school, and there was an identification with Israel as a result of that. And there were marches and so forth. And so, I think I felt culturally Jewish, because in general in England, I was feeling that I was the "other." I wasn't just Jewish; I was That Yank.
There are a large number of Americans who come to Oxford, but almost all of them are there for a second bachelor's degree, or a PhD or a Masters. So, if you go as a Fulbright fellow or if you go as a Rhodes scholar, or you go as a Marshall scholar, you're basically taking in a second degree. I was one of, to my knowledge, only two undergraduates at Oxford. True undergraduates who were taking their first degree there, who were from the United States. So, I was a very rare bird, and I think most of the "other" in culture that I experienced had nothing to do with being Jewish, and it had to do with being American. For example, two stories there. One is that I had my family send me a frisbee because we loved to throw frisbees around in the United States, and there was an absence of frisbees in England. Some English were familiar with frisbees because it turns out small versions of these had been distributed in the sixties in cereal boxes in England. And so, they recognized these things as being large versions of the toys that came in their cereal boxes. I had, you know, like an Olympic-size frisbee, and was out there, and so I was throwing this around with my friends, and the next day in the porter's lodge- on the way in at the Oxford's colleges, there's a, it's called a porter's lodge, the porter would greet you. He was a gentleman who would check everybody coming in and out and perform services for the college. Essentially a receptionist. Outside of the porter's lodge, they would post notices to the undergraduates. There was a note from the college bursar which said, I remember to this day, it said, "Gentlemen shall not be seen with flying discs upon the quad."
So, I got banned from the quad for throwing frisbees. And then there were other Americanism that I sort of got in trouble for. But I was mostly known for that. The other thing I did was, I started to play music. I'd always played guitar to some extent. In high school, I was part of the last bit of the folk era, I would fingerpick guitar, I played a little classical guitar, sang some Bob Dylan tunes. But at the time, I was starved for American music, because they were starting to play what was then the predecessor of punk rock music. And so, you live in your rooms on the staircase, and I would hear this music that I couldn't stand. I'd write off to my sister, who was at the time at University of Colorado in Boulder, and said, "You've got to send me some American music on tape." We had cassette tapes. And so, she sent me two albums which transformed my life. She was going out with a guy at the time who was into bluegrass music. And he sent me two tapes of bluegrass albums. One of them was Earl Scruggs' Foggy Mountain Banjo album. Arguably Earl Scruggs' most famous instrumental album. And the other was, it was after bluegrass came a new strain called newgrass, and she sent me New Grass Revival's first album on Starday Records, which had Sam Bush on it. He's a famous mandolinist. And Courtney Johnson playing the banjo. And I listened to this and my jaw dropped. I thought it was the most amazing music I'd ever heard. And so, I was determined to learn to play banjo. But I was also interested in folk music, and I informed my college roommates that I was going into London to Charing Cross Road, which is the place in London where all the music stores are. Not music sales but music instruments. And I told them that I was probably going to come back with a banjo or maybe I might come back with a set of bagpipes, because those were also interesting to me. And they told me if I came back with a set of bagpipes, they would wrap them around my neck and throw me in the college lake. And they were not joking (laughter). So, I came back with a banjo, and I started slowly teaching myself from these cassette tapes and Earl Scruggs had written a book on the banjo with a very famous banjo player, Bill Keith, who had actually done all the true transcriptions of these. And so, I started working on Bill Keith's transcriptions of Earl Scruggs' banjo and at first, I was just terrible. But we formed a little band. We called ourselves the Pheasant Pluckers. It comes from a British saying, which is, "I'm not a pheasant plucker, I'm a pheasant plucker's son. I'm only plucking pheasants 'til the pheasant plucker comes."
Now, if you get really drunk, it doesn't come out sounding like that.
(Laughter) I was going to say.
So, it's kind of a British test for sobriety. Anyway, we were the Pheasant Pluckers. And of course, I was the only Yank in the band, so I wound up being the front man for the band because I spoke with an American accent. The lead singer of the band turned out to be a guy who was at Oxford who had been in the [Maudlin] Boys Choir. And our bass player in the band was actually the lead cellist in the college orchestra. He had a (inaudible 51:47) who'd died and willed him a bass, except he didn't know how to play bass. Bass is tuned in fourths; the cellos tune in fifths. So, he had his bass restrung in fifths like a giant cello, and he played it that way. And sort of stringing it backwards, if you think about it. And I had an amazing fellow physicist, actually, who was in my same year who played the violin and he had an extraordinary ear. You could play him something. He'd say, "Wow, play that again for me." And you'd play the record again, and he'd pick up his fiddle and almost note-for-note he could capture what he'd just heard. And I haven't found anybody since who could do it quite as well as that. So, we had our little band, and we would play BBC 2 Radio Oxford and they have balls at the end of the year at Oxford, and so I made a little money doing that. And then when I came back to the United States, and there's a longer story there, but when I came back to the United States, I eventually started getting better and better at the banjo. This ultimately culminated in the "apotheosis" of my banjo career. In 1978, I came in second place in the U.S. National Banjo Championships, which are held in Winfield, Kansas. And at that time, I was living in Boulder and playing in another band there. So, bluegrass music became a big part of my life. When I moved out to Caltech eventually in LA, I used to go to a place called the Banjo Cafe in Santa Monica. I was a columnist for Banjo Newsletter, which is the national banjo magazine, and I'd written a column about the Banjo Newsletter, and one day while I was at the cafe, a waitress comes up to me to talk to me about this column I'd written praising the Banjo Cafe, and today she's my wife of thirty-five years. Kathleen. So, I owe my wife to bluegrass music (laughter) and probably my sanity as well. Because when I'm not doing science, I have a lot of good times playing music. I don't just play the banjo. Back around 2000 or so I switched to mandolin, and so I play a lot of mandolin. So that's, as we've talked about before, this is from my mother's side of the family, the music.
Right, right. Where did oceanography and Chinese language and literature go?
Well, oceanography got frozen out because, as I mentioned, you couldn't take oceanography classes until your sophomore year at Washington, so I never got to take a class in oceanography and that never happened. But I still had in the back of my mind a passion for living organisms, and an appreciation for their complexity and their diversity and a real interest in the physics of how living organisms could adapt to environments. For example, whales and fishes. So, there was that. Chinese language was left behind, because I got frozen out of that by being at Oxford, where I only studied physics. And I spent my first year there working like the dickens just trying to catch up with my colleagues. You only have two exams at Oxford. It's an interesting system. Or at least it was then. I think it's still this way. What would happen is that at the end of your three years there, you would take finals. Final exams. They're very unlike American finals. They consisted of a three-hour exam in the morning and a three-hour exam in the afternoon, every day for six days straight. So, they would test you on absolutely everything you'd learned. And there was only one other set of exams that you had to pass at Oxford, and those are called the "mods," which stood for Honours Moderations Exams. Incidentally, the results of both mods and finals were published in the London Times. So, this was the- that's why it was called the First Public Exam, mods, and the second one was, finals was called the Second Public Exam. So, you would take-- mods is a civ exam. It was designed to find out if you could continue at Oxford, or if you'd fail out. So, at the end of the first year, you'd take this exam, and actually a couple of my colleagues failed it and were out. And the grade on mods only matters if you, when you take finals, you happen to be on a borderline grade. So, in the event that you were a borderline grade, your grade would be modulated, that's why they're called Honours Moderations Exams. Your grade would be moderated to the higher or lower score if you did exceptionally well or exceptionally poorly in the mods. Other than that, you simply had to pass it in order to continue at Oxford. So, I actually went to something called a college reading party up in the Lake District before the mods exams to study hard for these. And mods for me were the hardest set of exams I've ever taken in my life. Not the finals, the mods. But I passed mods and so I was able to stay at Oxford. But again, you only study one subject, and so I had to leave Chinese behind, I had to leave oceanography behind. But I maintained an interest in these things. And in my final year at Oxford, or for reasons that are still not clear even to me, I took the theory option, and so even though I'm not a theorist and never wanted to be a theorist, but I always loved challenges, and they told me this would be the challenging thing to do. And so, I, okay, I did it. I think I partly did some of these things because so many times in my life, people have doubted that I was able to do it, and so it was kind of my way of saying, "In your face, I can do this." So, I took the theory option, but that was mostly about things like particle physics. And I looked around, and where were physicists working in particle physics in those days? Well, they were working on bigger and bigger experiments. The experiments of my father's era were half a dozen people. By this time, the collaborations at CERN, today on the LHC, for example, are thousands of individuals. And even back then on the intersecting storage rings, the ISR, they were several hundreds of people. And I didn't want to be, you know, one person on a hundred-author paper. That was not my idea of science. And the other thing I didn't want to do is I didn't want to go through life being known as Marty Block's son. That was really important for me to be able to establish an independent path. Because up to that point, if I was in a physics setting and I go up to someone, and we'd begin a conversation, if they were an established professional, we'd eventually get around to the point in the conversation where they'd say, "Are you Marty Block's son?" And I'd have to say, "Yes, that's true." So, I looked around, and I decided that biophysics was potentially very interesting to me. Now, I'd never had a course in biophysics. I'd never read a paper in biophysics. I really didn't know anything about it, but I thought perhaps that given my love of nature and organisms, given my interests in the outdoors through skiing and other things, that maybe I could somehow combine my interest in physics with other interests. And so out of the blue, in my last year at Oxford, I wrote off to a series of physicists who'd become biologists. So, none of these people knew me, but the essence of my letter was, "Hi, I'm about to graduate with an undergraduate degree in physics from Oxford. I'd really like to get into biophysics. What do you suggest? Maybe I could come work for you." That sort of thing.
And Steven, I'm curious, what was your classical training in biology at this point? Were you entering into a brave new world?
None whatsoever. The only biology I'd had was I actually, back in high school in Evanston, Illinois, I had one biology teacher who was African American, by the way. And who taught me, you know, and everyone else in the class biology but again, in one extraordinary weekend, decided to take a few students from the class and do something special. And we isolated DNA from cat thymus gland. Today, of course, you could do it with baggies and from strawberries, and it's an exercise that kids do in grade school. But back then, it was a pretty complicated thing do to and we had to go to the butcher's and get the thymus glands, meet at the professor's house for the weekend, and we did this. So, I think that sort of stuck in my mind. It was another one of these little glitches of memory that sort of stay with you, you know, ten, fifteen years later, and you still remember you had a good experience doing that. But the truth be known, I had no biology background, no training and background, no knowledge of biology, when I wrote off this letter. I just knew that I wanted to do something related to physics and it had better not be particle physics.
Right. And in addition to, you know, defining your ambitions negatively as, you know, in terms of not becoming, just staying in your father's footsteps. In terms of the biology track, were you also interested in taking part in research that would advance human health? Was that part of the equation also?
Well, I think the popular answer would be yes, but the true answer is no.
At the time. I mean, that's what I'm asking. At the time.
At the time. Of course, today, I'm very interested in advancing human health, and if I could do anything that would help with SARS-CoV-2, I would be actively involved in that. I was not, if I'm being totally honest, I was not motivated by anything to do with human health. I didn't want to be a pre-med. I didn't want to be a doctor. In fact, I had a kind of healthy disdain for doctors. Which has been nurtured, by the way, over the years. As a postdoc at Stanford, I actually helped teach classes in histology for the med school students. So, I'm well-aware of what med school students know and what they don't know. And most of them don't know. Doctors are strange beasts. It turns out that the placebo effect is enormously important in medicine. In experiments that have been done, as many as thirty percent of the people responding to simply a placebo will report some improvement in their condition. This not only holds true for medicines taken orally, but people have done experiments even with sham surgery. Sham arthroscopic surgery on the knee. And people report improvement after fake surgery, simply because they believe it helps. So, doctors know this and have known this for centuries. And what's very important in the medical world is bedside manner. What's very important is your doctor express confidence that he and you, with you as the patient, will get through this thing. That he and you will cure this. That you will become better as a result of his ministration. And if they fail to do that, chances are you won't get better, even with the best of medicines. At least statistically speaking. So, doctors are in the professional business of lying to you. They're in the professional business of trying to make you feel better about yourself and about the treatment plans that they have. They are often less than sanguine about the downsides. They are often playing up how much they really know. Like, "I've seen this before, I've seen many people get better. This is, you know, don't worry about it, we'll get you through this," kind of attitude. And my frank impression of that was very negative. It continues to be to this day because I know what doctors don't know, I know what the sorry state of medicine really is. Modern medicine is scientific medicine, that's true, but there's a big aspect of medicine which hasn't advanced in four centuries, and that's the psychological side. And doctors will be frank about this and tell you that psychological side is terribly important. But I didn't want any part in that because I considered it to be terribly un-scientific. And even as a patient to this day, I'm probably a terrible patient with my doctors because I actually want to know the truth, and with today's internet, of course you can research things up the wazoo. I'm not a hypochondriac, on the other hand I want the unvarnished truth. So, doctors are not prone to do that, and as a profession, I have a tempered respect for the things they do. So, I wanted to go into science. And if, so back to your question, I wanted to go into biophysics, and it had nothing whatsoever to do with the health aspects of the medical side. In fact, I didn't want to work on humans. I was interested in finding out something fundamental. So, back to my story, which is, I wrote off all these letters, and I heard back from very few people. And the one or two I did hear back from were negative. But I got one letter which changed my life. And that letter was from the late Max Delbrück. Max was a Nobel laureate. One of the founders of modern molecular biology. You can read all about his background in books like Judson's eighth day of creation, for example. Max was a physicist trained in the Copenhagen school. Worked with Lise Meitner and others. And read Schrödinger's What is Life book in the twenties. And actually came to the United States, first to Vanderbilt and then later to Caltech, and received the Nobel prize not so much for what he nominally got it for, which had to do with discovering that genes were random, or mutations were random, rather, but he got the Nobel prize for founding a school of thought. He surrounded himself with a large number of individuals trying to look for physical principles that could explain life. And those individuals included people like an early Jim Watson, George Gamow, who's the son of- or sorry, Igor Gamow, the son of George Gamow originally, and then later his son. Seymour Benzer, and others, and Max was a force of nature. And he founded the course at Cold Spring Harbor Labs in New York. And for many years taught all sorts of people about microscopic life, about viruses, about fage in particular, or bacterial viruses, about bacteria. And from his work stemmed a large number of individuals who later founded the whole field of molecular biology. And Max was growing towards the end of his career at this point. After he got the Nobel prize, which was mostly for work the so-called "t-fage," he started to work on something called phycomyces, which is a phototropic mold. It's a mold that it makes single cells, but those single cells are as long as your finger, except they're extremely narrow. And they have a panoply of responses to the environment. They respond to light, they respond to gravity, they respond to touch, they respond to wind. And he was interested in studying sensory transduction in these organisms. Anyway, long story short, and this is a long story, I got this letter from Max, who basically said, "Well, I teach this course at Cold Spring Harbor every summer, I have a lab there. Why don't we see if you're any good? Come to Cold Spring Harbor." And so, I literally flew from Heathrow Airport to JFK in the summer of '74, took the van across Long Island to Cold Spring Harbor, and spent the summer of 1974 at Cold Spring Harbor Labs. Which was total immersion baptism in biology. A fabulous place. Biology has, the marine biological labs, and it has Cold Spring Harbor Labs in New York. Physics has, you know, École de physique des Houches in France and it has the Aspen Center for Physics. So, I spent my summer immersed in biology, learning a huge amount, and working for Max Delbrück. It was at that point that I really decided that biophysics was what I wanted to do, and so I went to Max and I asked him what I should do. And he looked at me and said, well, I worked out, actually done some derivations to decide how phycomyces should bend in response to ultraviolet light based on the orientation of its photoreceptors and this involved integration and some trigonometry and some vector calculus, and because I'd had taken the theory option, after all, this was what I was going to do. But I was fascinated by experiments. And Max said, "You know, what you really need to do is learn some biology, because you really don't know any biology." I had no formal training in it whatsoever. I'd had no college training in biology. Last courses, as I'd mentioned, was in high school. So, Max said, "Well, you know what you need to do? You need to come out to Caltech," which is where he worked. "Come out to Caltech for a year, take some classes, read Watson's book." By which he meant the Molecular Biology of the Gene, not the double helix (laughter). Although I read them both. "And after that, apply to college, to grad school in biology." And I said, "Max, that's great, I'd love to do it." And he says, "There's only one problem." And I said, "What is that, Max?" And he said, "Well, I don't have any money to pay you." And so, I basically said to him, "Well, look, Max, I've got some money in savings, maybe my parents can help out. You know, I would love to come out and intern, basically, for you for a year." And he said, "Well, let me think about it." Well then Max did something truly extraordinary. Max had been invited, as a Nobel laureate, to come to the University of Konstanz in Germany on the Bodensee to give a series of lectures about his work, and he'd originally turned them down, but he called them back and said he was coming after all, and he did this because he took the rather large honorarium they were promising him and he turned it into the Steve Block fund. And he came back to me two days later, and said, "Don't worry, I've raised the money. You can come with me to Caltech next year." So, I owe this man my career. I owe this man my livelihood. I owe this man a debt of gratitude that I'll never repay.
Yeah. And when you say you worked with him, you really worked with him. Not his postdocs?
I really worked with him. So, I was not a postdoc. I wasn't even a grad student at that point.
No, I'm saying you didn't work with his postdocs. You really worked with him?
I worked with Max, and with his post docs actually, so he brought me out to Caltech for a year, where I was literally the dish washer for the group. I washed and sterilized the dishes; I ran the autoclave. I made potato dextrose ager, which is the medium that you grow phycomyces in. But on the side, he had a post doc named Ed Lipson, who eventually went to the University of Syracuse. And Ed and I did experiments. Ed had built a tracking microscope to follow the growth of phycomyces in real time, and you could stimulate it with light and it wouldn't see the red laser light, and so you could bounce red laser light off of it and measure its growth very, very accurately in real time in response to stimuli, and I did all these experiments on phototropism and the light response in response to different colors of light. At the end of the year, I had almost a paper done which eventually got published, with Ed Lipson, who was Max's post doc. And oh (inaudible 1:11:42), the other thing I did of course is I started applying to graduate schools. I took the GREs in physics and thanks to the training I'd received at Oxford, got a sensational score on the GRE, because I took it in physics, not biology. But I applied to biophysics programs all over the country, and to my astonishment- well maybe it shouldn't have been to my- thanks to Max's letter of recommendation, I got into everywhere. Including Harvard, and especially including Caltech, where Max was, because frankly I just wanted to stay at Caltech.
Did he encourage you in any particular direction?
Well, so, that was the next thing that happened. So, I'm wandering around, trying to figure out where to go. Max sees me in the hallway, and this is in the basement of a building at Caltech, where I was working on these experiments, and he says he wants to talk to me. So, we go to my office, and we sit down. He looks at me and he says, "Steff-" He called me 'Steff.' "Steff, I want you to go to Colorado." And I said, "Why should I go to Colorado, Max?" And he says, "I want you to work for Howard Berg." So, it turns out, unbeknownst to me at the time, Max was on his last legs. He'd been diagnosed with a brain tumor. He was to die a year or two later. But he was really enamored of the work of Howard Berg, who was at the time at University of Colorado. Burke was also a physicist. Trained with Norm Ramsay on the hydrogen mesor at Harvard. Got interested in biochemistry and was one of the people who actually invented, or co-invented, the SDS gel that we use today to separate proteins. And then got very excited about chemotaxis and e. coli, the motion of the bacteria towards chemicals they liked and away from chemicals they didn't like. And he worked on a number of experiments, and he too had built a tracking microscope, except this one could follow the motion in the individual micron-sized bacteria as it swam in real time. And he developed this at Harvard and then moved to the University of Colorado shortly after the formation of the new department there, which is still going to this day. Just celebrated its fiftieth anniversary, and that's the department of molecular, cellular, and developmental biology at the University of Colorado. It was my honor to have been invited to their fiftieth celebration as one of their proud alumni, I guess.
Now you mentioned you had a sister, was she still in Boulder?
No, she'd long since graduated and moved away and was living elsewhere, so I had no relatives there, although my parents of course spent, at that point, all their summers in Colorado, in Aspen, which is on the other side of the Great Divide, so it was a good three-and-a-half-hour trip from Boulder. But Max basically had an arranged marriage for me. He was, it turns out to be, he was a big fan of Howard Berg's. There's a famous quotation from Max, which I probably should mention. He spent twenty-five years looking at this phototropic mold, phycomyces, which turned out to be a mess. It has multiple nuclei, not just one, it's genetically extremely difficult to work with. It has a sexual cycle, but it takes months to go through. And so, to work with it from a genetic standpoint was a nightmare. It has many complicated responses to this day. We still don't know most of the work. And you really couldn't pick it apart as a model organism. But there was another famous biologist by the name of Julius Adler at University of Wisconsin, who went back and read some papers from the 1800s from people like Pfeffer and Englemann, and re-discovered the fact that e. coli, the darling organism of biology, actually had a large number of sensory responses, chemotaxis. And why was nobody working on this? Well, it turns out that the strain of e. coli which was being used in laboratories all over the world and had been grown for so many generations in the lab, that it had lost all of flagella, so it couldn't swim. So, nobody noticed any sensory responses because they had immobile bacteria. So, Julius Adler went back to the sewers of Wisconsin and re-isolated e. coli after all to get a truly wild type strain. It was called AW405, which stood for Adler Wisconsin 405, and that became the prototypical strain for working on e. coli. Howard Berg spent some time with Adler and got excited about this and started to dedicate his career to understanding chemotaxis. To this day, Berg has published some of the best papers on e. coli chemotaxis. And he's the man who discovered that bacterial flagella literally rotate like props on a submarine, but they're driven by a rotary motor at their base, which is in turn powered by an electric current, actually, and its so-called proton mode of force. Protons pass through this motor driving it around in rotation. And I did my graduate work on that motor, most of it. Thanks. But back to our story, someone once asked Max Delbrück why, since he was interested in sensory rotation, and since he was famous for picking great model organisms like t-fage and e. coli, why didn't he just use the same E. coli he had all along to study sensory transduction? Why did he work on phycomyces, which turned out to be something of a dead end? And his famous answer was, "I didn't know how to tame them." It's somewhat inscrutable that that was his answer.
How does one tame-
Anyway, if anyone could tame them, it was Howard Berg, and he was the person, as I said, who built this tracking microscope. So, after Max told me to go to Colorado, I tore up my applications to, or my acceptances to Harvard and Caltech and other places. I went to Colorado only to discover that everyone in the freshman- sorry, freshman would mean the first-year graduate student class, was doing rotations through different labs. But not me. It was understood that I would be working for Howard Berg. There was practically a nameplate on the desk with my name on it. So I began working with Howard Berg, and this was also ironic because when Max subsequently passed away a few years later, I guess it must have been four years later or thereabouts, Caltech is looking for a biophysicist to replace him, and who do they get but Howard Berg from the University of Colorado? So, I was a human yoyo. I spent my first year in Caltech, but I also finished my PhD in Caltech with Howard Berg working in a laboratory very near where Max had worked. So Max was formative in my career, but then Howard Berg is the next major influence in my life. He was a tremendous influence. Because although I was excited to be at Colorado, and very interested in the system of bacteria and chemotaxis, I was also lazy and easily diverted. In Boulder, there's an enormous community of folk musicians and bluegrass musicians, and so I joined that community and I would spend my summers traveling around the country in a Volkswagen camper bus playing in bluegrass festivals, entering banjo contests, winning a few of them. If I won enough money, I paid for gas to go to the next festival. And I was supposed to be in graduate school doing research. And Howard Berg, I don't know why, ever tolerated some of this behavior. Behavior, incidentally, and hypocritically, I would have never tolerated in my own graduate students. But he allowed me to do this and of course, in the winter sometimes I would go off and go skiing and come back a week, or two, or three later. Back in those days, if you bought it before early November, you could actually get a ski pass to Eldora, which is the local ski area outside of Boulder. And you could take a bus from the Boulder Library up Boulder Canyon and go skiing. So, I would work until three or four in the afternoon, grab my skis, go to the bus station, and take a bus up to Eldora, where they had night skiing. And I would do night skiing then come back, collapse in a lump, and then drag myself rather late in the morning into the lab the next day. So, this went on for a few years. My band got more popular, I got better on the banjo, I won that contest I told you about. A national banjo contest, I won second place. And then Howard went off to Paris for a year on a sabbatical, but before he left, he sent me a note which I don't have, I should have saved it and framed it. But it was a note to the effect that, you know, "Well, Steve, you know you're bright and all. You have the potential to do some great work. But unless you decide to buckle down and get something done, you're never going to get anywhere." And that note shook me to my core. So, I underwent a kind of phase change in my activity, and that phase change was aided and abetted by the fact that Berg eventually left Boulder to go back to Caltech, because he was taking up a biophysics position there. And I moved with him and the lab to Caltech. And this would have been in January of 1980. And unlike Boulder, where there were ultimate distractions, everyone at Caltech was in the lab. You could open the building at 10:30 at night and half the lights would be on in the labs, and people would be working there. So, it was a totally different environment. But I went with it. Spurred in part by Max's, I'm sorry, by Howard Berg's encouragement, if that's the word.
Steven, I'm curious, at this point are you comfortable enough in biology where you're not learning everything on the fly? You've established your sea legs in the field?
Oh, absolutely, and in fact, my degree from Caltech is actually on the biology side. So, I technically have a PhD in biophysics. At Colorado I had to take a lot of courses in biology. I got really interested in biology to the extent that the graduate students on their own, and I was one of them, established our own course called Bioenergetics. Which for many years was taught at Colorado after I left. So, we even, so not only did I take classes, I actually wound up teaching classes. And I also, believe it or not, I also took my PhD qualifier twice in biology. So, when I was at University of Colorado, I was about to leave, they said, well you're leaving without a PhD. You could take a master’s degree. But that required taking the PhD qualifier, so I sat those exams. Back in those days, you also had to take a language exam. It was part of your PhD. So, I did it in French because I was good in French thanks to my years in Switzerland, in school there. So I took that, and then when I got to Caltech I thought I would automatically be enrolled in their program, but they were not willing to do that even though I was Berg's student, without my taking the quals in biology at Caltech. So, I took the quals in biology at Caltech as well. So, by the time I was a postdoc, I was completely retrained in biology, and arguably knew as much or more molecular biology as the next person.
And in terms of the day-to-day, where you using physics or was this really, truly immersed in a biological world?
It was truly immersed in a biological world, and I think it's fair to say, even to this day, that it's probably easier to teach biology to a physicist than it is to teach physics to a biologist.
Right. I've heard that. Yes, yes.
And the difference, there's a kind of difference in the field itself, which I might describe in the following way, which is that physics is in some sense a vertical field. The best theorists can often derive everything they need from a few simple assumptions and a knowledge of some basic equations. It's not quite that simple, but back of the envelope physics of course is very, very powerful. And in fact, later in my career I was to intersect with Ed Purcell, who was the quintessential expert on back of the envelope physics. And but it's possible in physics to develop a simple understanding of things, and then make it complicated from there. And you can do this with a good knowledge of basic physics and not a whole lot else, except some native smarts. And so, physics is in many ways a vertical field. Even the best experimental physicists have some knowledge of the materials, material properties, measurement techniques, but they also build on things they know. And so, I would describe physics as a vertical field. I would describe biology as a horizontal field. There's a huge amount of information, and the best biologists are able to bring very disparate information to the bear on a problem and gain insight in that way. So, the best biologists are in many ways like a Jeopardy champion on TV. They have a huge knowledge of facts at their fingertips. And so, the kind of skillsets required are slightly different. But if you're smart and you pick up things and you remember things; you can be a biologist. And biophysics, of course, is an attempt to take the tools and the strengths and the precepts and most importantly the mindset of physics and apply it to biology.
So that's really the direction that you see? You don't see it going the other way? Take a mindset of biology and apply it to physics? That's really how it works in your mind?
The other direction can certainly happen in principle. it's extremely rare.
Is that simply because physics is more fundamental? It lends itself in that direction?
Well, you know, physics is said to be the mother of all sciences. And here's an interesting sidebar, which is that when you get your degree at Oxford, which I did, the degrees are awarded in a sequence. And they're awarded in the sequence of when the schools of that subject joined Oxford as a university. So, the first degree awarded is theology. The second degree awarded is English, because rhetoric was one of the first things, but the third or fourth degree, I can't remember which one it is, is physics. And you can ask why. Well, physics wasn't called physics. It was called experimental philosophy.
And I can think of no better name for physics today than experimental philosophy. Because that's what it really is. We use information and evidence in the real world around us to try to understand how that world works. There can be no more fundamental and no more noble pursuit of information in my view than that. So that's why physics is so important to me. It is really the pursuit of knowledge in its most fundamental form. And so of course that can apply to biology as well. Biology, by the way, in case you didn't know this, is also a very new word. If you read Darwin's Origin of Species, for example, the word biology doesn't appear in it, it was coined later by the Germans. And it joined our language relatively late. Physics, by the way, is not a great word if you think about it. It's certainly not as noble as experimental philosophy. So, back to our story, what we were saying, the physics that I do has been always characterized by trying to understand the sum of fundamental way, how something in nature works. And most of my career has been trying to understand how molecular motors work. So, we are propelled, you know, your muscles contract, and your brains think, and all these things happen, as a result of a series of proteins which have evolved to the point where they can actually produce movement. And so insofar as there's a common thread working through my career, it started in sensory transduction and it's in phycomyces. I transitioned to sensory transduction in E. coli, understanding their chemotaxic behavior, which drew me to their motor, because their chemotaxis is carried out by driving their motor clockwise or counterclockwise depending on the sensations they're getting in a probabilistic fashion. So that got me interested in their motor, and then as a postdoc, I started first working on their motor, then I moved into myosin motors in the postdoc at Stanford, and eventually into kinesin motors when I started working independently as a scientist. And then from there back to the fundamental enzymes of life, including RNA preliminaries, which is the enzyme that reads the genetic code, which is also, if you think about it, a motor that moves along DNA transcribing RNA as it goes. But being a motor is an integral part of its process, so my whole career has been looking at the production of motion in nature, which of course requires energy, and how is that carried out at the molecular level? So, this is the perfect job, in my view, for a biophysicist, because it combines trying to understand aspects of the physics of the motion, trying to understand how energy is transduced in order to get this thing to work. Trying to understand how such motors can interact with cofactors who work in purposeful ways and how they're regulated in cells and so forth and so on. So large organisms are built out of small components and I think there's a new appreciation for those small components. Particularly, as I say, since I got my start with one of the founders of molecular biology. Molecular biology got started when there was a return to an understanding that when DNA was discovered, and then eventually the structure was solved by Francis Crick and Jim Watson, thanks to Rosalind Franklin in many ways, let's not forget. But when this kind of information came about, it resulted in a renewed emphasis on understanding the control of genetic information and the processing of genetic information. The flow of information in cells. And then how organisms were built up from constituent parts. And so today a lot of biology is concentrated not at the organismic level, not the people with the pith helmets and the butterfly nets, but rather people, often physicists, who are working at the level of single molecules.
So, Steven, I want to ask you the same question at a different narrative inflection point in your career. You know, I asked you about possible interests in human health research. When you first sort of had that, you know, "Maybe I'll pursue biology." And you gave me your answer there. And now in terms of the narrative of, you know, the arc of your career. You've finished at Caltech, you've defended your dissertation, you're now onto your postdoc. And of course, this is really the time when you start in a systematized way to develop a professional identity. You know, the kinds of things that you want to work on long-term. And so that same question, do you have the same response as a postdoc at Stanford? That your attitude and your research agenda is still very much in a basic research framework, or is human health science sort of a more focused motivating factor for you?
To this day, human health science is not a motivating factor for me. I suppose I'm true to my physics roots. I'm really interested in how things work for their own sake. I want to understand how biology derives such exquisite complexity from simple parts. How those simple parts interact. One thing we've gained an appreciation for is that proteins are little machines. And they're nanoscale machines. They do nano biology or nanotechnology much better than any human has ever done nanotechnology. And they are atomic scale accurate. They're reproducible and I have the deepest appreciation for these machines and how they work, and, in many ways, I've dedicated my scientific career to trying to understand better how that works. This is a fundamental question. If it has immediate or even indirect applications to human health, I'm all for that, wonderful, mazel tov, go for it.
But that's not what got you into it in the first place.
But that's not why we do it, exactly.
Once reminded of Feynman's famous quote about physics, which is that physics is like sex, sure, it has some fruitful outcomes, but that's not why we do it (laughter).
Well, now that's confirmed, because now you're the second person that I've heard that quote from. So now I know it's real (laughter).
Well, I may have garbled it a bit, but that was the sense of the quote. And the fact of the matter is that I'm interested in biology for what it can teach us about the world around us. And you know, why do particle physicists study particles or why I think they're interested in what is truly fundamental in this world, and in the fifties it was particle physics and then it was quarks, it's QCD, and today it's string theory and other attempts to try to understand at a truly fundamental level what is matter and what are the forces that engage matter? And of course, that's also active on the cosmological scale. So, physics is interested in all scales of distance, but the most exquisite example of complexity we have are living organisms, including ourselves. The fact that we can even understand ourselves is almost not understandable, and so my interest is to try to de-mythologize some of that and to try to understand better at a level of complexity which is well up from atoms and well up from even simple molecules. But the level of biological macro molecules, which have you know hundreds of thousands of degrees of freedom and are in fact quite complex in their own right, how these molecules can interact and produce very sophisticated kinds of behavior. Including in the case of motors, the production of displacement and force in motion. So, how does this happen? And of course, this happens by burning energy, and there are broadly-speaking two classes of motors in this world. There are those that use the proton mode of force, protons. That includes of course the bacterial motor we talked about. It also includes the device that makes most of the ATP in your body, the ATPase, which is responsible for energy production, and then of course once the ATPase has done its job, we have lots of ATP, and so the ATP is then in turn used to run other classes of motors like myosin, which makes your muscles contract, kinesin, which ferries cargo in your nerves and brain and other places, pulls the chromosomes apart in mitosis. All these motors need a source of energy, but it's probably fair to say that the molecular mechanism by which any of them works is not fully understood. It's being worked out in our lifetimes.
When you got to Stanford as a postdoc, were you looking to expand on the research that you had already done, or was this an opportunity for new projects?
So, the research I'd done at the end of my career at Caltech was really in many ways responsible for everything that was to follow. This was with Howard Berg, who as I say, after Max Delbrück, had this incredible effect on my life. I owe the start of my career to Max Delbrück. I owe the meat of my career to Howard Berg. Howard Berg was interested in this motor. One thing you can do with a bacterium is you can do what's called tether it. You can take a bacterium, break off most of its flagella. They're very brittle so you can do this by hydronamic forces. And then take the stubble, which is a little piece of one flagellum that's sticking out and stick it down to a piece of glass. You can do this with an antibody, but there are other ways of doing it as well. So now one end of the flagellum is stuck to the glass, and the bacterium tries to turn its motor, and the tail wags the dog. And the body of the cell goes round and round and round in circles. Now the motor has a gear shift, so the motor, it will drive the bacteria clockwise for a time, about a second on average. And then it'll switch gears and drive the bacterium around counterclockwise for a time. And the clockwise versus counterclockwise behavior gets modulated and that's ultimately, it turns out, how a cell is able to move up gradients of chemicals. It runs and then it tumbles and runs and tumbles and runs, turns around to correspond to counterclockwise rotation, and tumbles and turns to correspond to the clockwise rotation. This was all worked out by Berg in the 1970s. And the details of how that works are another topic all together. But the bacteria have this gear shift and they have this motor, and it's absolutely fantastic. Well, it turns out the motor's made of about, oh, about twenty-five, thirty different components. Different proteins. It's about the size of a small virus. So, it's a very complicated thing compared to most other ones. And you can take these tethered cells and watch them go. If you take a cell which is missing one of two genes, their genes are called mot genes, M-O-T, there are two alleles, MotA and MotB, so there are two flavors of mot genes. If you're missing one or both of those mot genes, you make motors. You make flagella. You can tether cells. But the cells don't turn. Well, the experiment I did at the end of my graduate career was in combination with colleagues to put the mot genes, which a mot mutant is missing, under the control of a plasma, which is a little piece of genetic material, which is independent of the chromosome, and that plasma can be turned off, so it's not expressing mot. You tether your cell, and of course, the cell's not going to do anything because it doesn't have mot protein. Now you turn on the plasma, and the cells, after a period of anywhere from five to thirty minutes, starts synthesizing the mot protein itself. Now what you see when you look at the cell is all of a sudden, after twenty minutes of doing nothing, suddenly the cell starts turning slowly. Round and round and round. And then you keep watching it, and suddenly, boom, instantaneously, apparently, the speed of the cell doubles, and now it's going around twice as fast. And now you watch it some more. And then the speed trebles, relative to its first level. And then quadruples. And then quintuples. And this goes on and on until you're about, roughly speaking, eight times faster. Somewhere between eight and ten times faster than when you started. So, what you see are these steps in angular velocity. And the interpretation of this experiment is that the mot proteins are, if you will, the pistons of the motor. And when you have one piston in there, you have one banger, and you go around but slowly, producing a small amount of torque. When you add the second one, you produce twice as much torque, and since these cells are at such low Reynolds number, when you double the torque, you double the angular speed. In fact, the angular speed is linearly proportional to the torque. So, if you see eight increments in speed, what you're seeing is eight equal increments of torque. This experiment shows that there are force generators from the motor, they're independent, because when you add the fifth one, you see the same step in velocity as when you added the first one. And so, they work independently, they each generate a certain amount of torque, which you can measure. And you can learn a lot about the motor in these experiments. So, that got me excited about molecular motors in general. It got me so excited that right around the time that we were publishing this, another paper came out, and Jim Spudich, who is a professor at Stanford, in the medical school, had worked out an assay for taking myosin, which is the protein responsible for muscle contraction, and sticking that on the surface of actually little dead bacteria or little beads, and getting these myosin motors to move and drag those little beads along the filaments of actin. Now actin is found inside your muscle, it's the thing that myosin usually moves on, but the actin in muscle is very hard to work with. He discovered that there's a plant, it's an aquarium plant called nitella. It's big enough that you can actually cut it open, it's a cylinder, you can cut it open and lay it out like a flat sheet, and it would expose these actin filaments. So if you floated these little beads, which had myosin on their surface, down to the filaments, all of a sudden they would engage and they'd take off, and you'd know this because the bead which you can see would start moving. Even though you couldn't see the myosin and you couldn't see the actin because they're at the molecular level. So, this was the first in vitro motility system for myosin movement. Well, I've been working on an in vitro motility system for bacterial motors. And I thought, oh this is fantastic, I want to understand how myosin works, and someone has finally developed and assay for making this to work. By the way, Jim Spudich was later to win the Lasker Award for part of his development. So, I applied for a postdoc at Stanford, and I went in 1984, I believe, to Stanford. And I did my work there trying to understand the molecular mechanism myosin. There was a popular theory at the time for how myosin worked. There were many theories, this was just one of them. It was from a guy at Johns Hopkins named Harrington. And the suggestion was there was a part of the myosin molecule called the S2 region. The name isn't important. But the S2 region, he discovered by biochemistry, could move from an alpha helix, which is a long, extended helix of protein, to a random coil. Now, a random coil has its ends closer together than an extended helix. And he felt that by cyclically transitioning between a long helix and a short coil, back and forth and back and forth, that cyclic motion could drive myosin in steps moving forward. So, his, this was the helix coil transition model of myosin motion. Based on the so-called S2 region of myosin. So that was very interesting, but it also turned out to be testable. It was testable because we knew how to chop myosin up into pieces using certain digestive enzymes. And it turns out you can make something called heavy narrow myosin. It's a fancy name, but all it means is its myosin with the S2 region digested off of it. And the question was, well, could that little stubble, that little residual piece of myosin, which we knew still had the ability to hydrolyze ATP, and still had the bulky head of the protein, which was where we thought the motor was. It still had that, but it was missing the S2 region. Could we attach that to little beads and get those to move in the same way? So, the answer to that question was yes. They would move. And that immediately told you in a stroke that the Harrington model could not be right. That insofar as the S2 region did anything, it was not involved in the motility of the protein because you could get it to move even without the S2 region attached. So that was the end of that, and it was at that time that I started thinking that it might be possible to start to work on proteins at the level of single molecules. We were getting close, because after all in these myosin assays, we had in this case multiple myosins attached to a bead moving on an actin filament. But maybe you could dilute it down, down, down until you go to the point where your bead only had, say, one myosin on it moving on an actin filament? At that point, you'd be looking at a single myosin. And then wouldn't it be cool if at that point you could actually measure the force associated with myosin as of moving? Measure the power stroke. Measure to see if it moved in discrete displacements or moved continuously. If it moved, what force did it generate? How fast did it go? Could you measure the force-velocity relationship? Because that's after all what you do with a lot of motors. In your car, you know, you measure the horsepower as a function of RPM, for example. You put your car on a dynamometer, you measure how good the motor is by looking at its torque-speed relationship. So, for linear motor, that would be the linear velocity versus the speed. Sorry, versus the force generated. I misspoke. So, I wanted to do that but at the time, the assays didn't permit it. You could try to titrate, let's use the fancy word, the myosin would be down and down. It conked out before you got to the level of single molecules. And part of the reason for that is that it turns out myosin has what's called a short duty cycle, and it engages the actin filament quickly and then immediately releases. And so, if it releases, the bead can just float away if you just have one molecule there. So, what you really need is a bunch of myosins all in the bead. So statistically speaking at any given time, one of them was attached. That way you would contact the filament and just keep walking. But you're walking because perhaps twenty myosins are involved in the motion. And they're dragging each other along like the itsy-bitsy spider. And one leg is always in contact. So, myosin was not going to be great, but right around that time, around 1984, a new protein was discovered at Woods Hole by Mike Sheetz and Ron Vale and Bruce Schnapp and others. And that protein was named kinesin. And kinesin was also a molecular motor, a little bit like myosin but much, much smaller. In fact, to this day, I think it's the smallest ATP motor. Myosin (inaudible 1:45:57) ATP, kinesin does too. But kinesin has a different duty cycle. It stays attached so that the head doesn't tend to release from the filament. Now, myosin walks on actin, kinesin walks on microtubules. And so, it occurred to me that if we could find a motor with a high duty cycle, it might be possible to get down to the level of single molecules. And actually, see a single kinesin walking on a microtubule. And if you could attach the kinesin molecule to a bead, much as had been done for the myosin molecules, if you could put forces on that bead, then maybe you could watch single molecules step, for example, or measure their force velocity relationships or measure the forces they generate, and so on. So, that was the idea. And I was even interested in trying to do it with myosin at the time, people didn't know how to produce these kinds of minuscule forces to stop these things. So, one of the ways of doing this, I thought, would be maybe to attach a magnetic sphere to the bead and put it in a field gradient. Because, and I did some back for the envelope calculations. We didn't know at the time the exact force levels, but we sort of knew order of magnitude how they were going to be. And I computed that we needed really big magnets. You know, getting up to a Tesla or thereabouts. So I actually went off to talk to some of the physicists at SLAC who had helped develop the wiggler magnets for the free electron laser, and was talking to them about how do we produce magnetic fields and field gradients sufficiently large to produce these kinds of forces? And it became clear that I probably wasn't going to do it with a regular magnet. I would either need a superconducting magnet, which was not easy to integrate with a microscope, or I could do it, perhaps, with a permanent magnet. Because at the time, you know, the first really good permanent magnets were being developed, and boron and so forth. So, I was working on designs to try to adjust the strength of the magnetic field by having two magnets in cylinders and rotating them relative to each other and nulling out the field in one configuration and getting it to go the other. I had all these thoughts. But right around then I was finishing up my postdoc and it looked like it wasn't going to work. And it was just around that time that kinesin was discovered. So, when came-
Who discovered kinesin?
Who discovered kinesin? Where did that happen?
Kinesin was discovered by Ronald Vale, Mike Sheetz, Bruce Schnapp, and I'm missing one person, at Woods Hole in the summer, and it is a factor that's abundant in neurons. It was first isolated from the giant squid axon. Woods Hole is famous for the squid that used to look out there and a lot of the early neuroscience was done on these giant squid axons. So that was their specialty there. And there was also a guy named Bob Allen who was a famous microscopist there, who was involved in the early days in trying to track down this motor. There's a complicated and controversial history about the discovery of kinesin and who gets full credit for it, which is worthy of another story. Bob Allen unfortunately died of cancer, but he went to his grave very angry about the way in which kinesin had been discovered without full credit going to him, or at least partial credit. But it was Ron Vale more than anybody else who first cloned the kinesin gene after the protein had been isolated and has been a leading researcher over the years in kinesin studies. But I wanted to do the biophysics of kinesin, not the genetics and not the biochemistry.
And why did you recognize that kinesin was automatically a big deal for you in your research?
Two things. One is that an assay existed for it that where it could be moving little beads, because that's in fact inadvertently the way it was discovered. And the other thing was it had this high duty cycle as I was mentioning before. Myosin was a poor candidate, skeletal muscle myosin, one that we have in our muscles, was a poor candidate because this duty cycle was so low, so you could only watch multiple motors at work, you couldn't watch single motors at work. By the way, as a historical side light, since that time, new myosins have been discovered in the myosin family, which are in fact processive, and which do in fact have this high duty cycle, so you can do the same kinds of experiments with them as you can with kinesin. But these are not muscle myosins, these are myosins that are found in other contexts in organisms. But at the time, and this was 1985, kinesin was unique in that it moves slowly enough that you might be able to work with it. It looked like it might work at the single molecule level. And it had a high duty cycle. So, at that point, I was finishing my postdoc, and I had two options. One was to take an assistant professorship at Stanford, which I had been offered, and the other was to rejoin Howard Berg, my former advisor, who had moved off at that point from Caltech back to Harvard. And he also accepted a position at the Rowland Institute for Science. An amazing place founded by Edwin Land of Polaroid fame. So, Land held more patents than any human in history short of Thomas Edison, and he was a one-man R&D department for Polaroid, the corporation, for many years. First working on, of course, polarizing plastics, but later on instant photography. And he took his many, many millions and built a private science institute on the banks of the Charles River not far from Kendall Square, right where the red line crosses the river on the Longfellow Bridge.
And it was an independent institute? It wasn't connected with a school?
It wasn't connected with anything; it was purely for Land's own amusement. His family was very unhappy about this because his children had grown up, and they scarcely saw their father, his two daughters, because he was always off doing science and they thought that, well, finally he's retired, and they'll be able to see more of him. But no, he established this institute. People ask him where the name Rowland came from, and his usual answer to that was, "I'm not going to tell you." It is thought that partly it was a tip of the hat to Henry Rowland, who was the famous optics professor at Johns Hopkins, who invented the diffraction gratings that made possible. He invented the ruling engine, which made possible these diffraction engines-Gratings, sorry, that would allow you to do optics in a new way. It was also possibly having to do with the word "Land" itself, which is his own name. Or the fact that his son-in-law, who he was enamored of, had been quite a rower at Harvard. All these theories are still in play because Land went to his grave without explaining this. But what he had in mind was establishing a kind of Noah's Arc of science on the banks of the Charles. It was a private playground where he could do anything he wants. He had a machine shop staffed with the best machinists. He had a woodworking shop staffed with a superb carpenter. He had a private library, which had a Tiffany lamp worth god knows how much on the table, and he had two of everything. He had two chemists, two physicists, two biologists. And the idea was, apparently, that he would allow people to work for them to do anything they want, they had an unlimited budget to work on whatever science they wanted, but if he needed their advice or help for a couple of weeks a year, say, they would drop everything and work with him on whatever his pet project was, and then they could go back to doing whatever they wanted. And so, Berg had been recruited to this with the understand that when Land passed on, Berg would likely be the new director of the Rowland Institute. So, Berg called me up and asked me if I would be a co-conspirator, if I could use his words, and so I agreed. It sounded to me like paradise on Earth. I wouldn't have to write grants, I wouldn't have to sit on committees, I wouldn't have to teach classes. I could just do anything I wanted with whatever budget I wanted as long as it interested me, and then I would have an opportunity to interact with, you know, one of the more creative minds of the century in the form of Edwin Land, although at that point he was, you know, getting old and in poor health. So, I joined the Rowland Institute.
And Steven, was your sense that this was a place where you could collaborate with academic colleagues? This was not necessarily a research island?
Well, it was a bit of a research island. Of course, the beauty of being in Boston (laughter)-
-was that Boston is hardly a research island, so even if you're in a relatively isolated place within the city, you were ten minutes from Harvard, five minutes from MIT, and across the river from Mass General Hospital. And I had collaborations going on in all three places. So, from my perspective, it was lonely there on a day-to-day basis, because the building was really under-populated. It was a beautiful building, enormous indoor atrium with bamboo growing and the skylights and a greenhouse and spiral staircases and a place- it also had private apartments which were never open to us, but so Land imagined that he would have some visiting scientists, he'd put them up in luxury in these beautiful apartments, which had, you know, refrigerators and kitchens and lavish bedrooms and bathrooms with Jacuzzis. So, these were all a part of the Rowland Institute at the time. Land's own office had this enormous Sunrise at Albuquerque photograph by Ansel Adams, probably worth tens of thousands of dollars. Today maybe hundreds of thousands of dollars. A spectacular porch with a view across the river of downtown Boston and the Beacon Hill. So, this was quite the place. It was under-populated. So, it was both an island of isolation and not at the same time. So, I got there and right at the time that I was moving across the country, with a predecessor of today's laptop, I had something called the NEC Multispeed. It had two 720k floppies, which went into it to boot it up. And like a 12-line display, which was alphanumeric. No graphics at all. And I spent the time while my wife was driving, when I wasn't driving, debugging routines because Bill Press had written a new version of Numerical Recipes. He had written the Numerical Recipes in C. And so, I had a C interpreter on this thing, and I was running them all through this interpreter, trying to find bugs in his program. So when I got off in Boston, I went to see Bill Press, with a list of about ten or twelve things that were eventually corrected in the first edition of Numerical Recipes in C. I should say that I'm acknowledged in two or three textbooks, in their early editions. And I'm more proud of those acknowledgements in some ways than any of the papers I’ve written. I was acknowledged in (inaudible 1:57:46)'s Biochemistry, which is one of the great biochemistry texts of all times. I was acknowledged in an early version of Numerical Recipes. And I was acknowledged in another famous Harvard text, The Art of Electronics by Paul Horowitz and Winfield Hill. So that was great. So, I managed to touch in all these different directions. Anyway, the Rowland Institute was both, well, was a fascinating, fascinating place. And the fact that I had a carte blanche to buy anything I wanted was just amazing. And while I was traveling across the country, as soon as I got across, literally within a few days of being at the Rowland Institute, a very famous paper came out in Nature from Art Ashkin, who got the Nobel prize in 2018 for the invention of the optical trap, or optical tweezers. And this was a paper in Nature in which he discovered that by using the right wavelength of light, you could actually capture individual bacteria and move them around under control of the optics. I thought this was the greatest thing ever. But the fact that he could capture e. coli, which were swimming, was interesting to me, because I knew the force of swimming of e. coli. I'd worked that out many years ago. And I realized that we were talking about piconewton scale forces here. But piconewton scale forces were precisely the forces that I wanted to engage on individual motor molecules in order to watch these molecules slow down and ultimately stall. If I was going to measure the stall force of a kinesin or myosin, I needed to have of order of ten piconewtons. So of course, the exact number was not known, but you know, fireworks, not just light bulbs, went off in my head when I read this Ashkin paper. I thought this was just amazing. So, I'd just arrived at the Rowland Institute, and first thing I did, I started looking into a solid-state laser that would produce enough power to be an optical trap. The next thing I started to do was trying to design how my own optical trap would work. And the only thing I had to go by was this god-awful picture that Ashkin had published in his Nature paper. The problem with Nature at the time, it's not true today, but back then, there were almost no materials and methods in the papers. Materials and methods were relegated to the last part of the figure legends. So, every figure legend had at its bottom four or five sentences explaining the methods. So, all I had to go on was four or five sentences and this diagram. Which, of all things, showed a negative lens and then showed the laser going into, of all things, the eyepiece of the microscope. Well, that's kind of weird because if you're trying to look at the microscope, how would you do this if a high-power laser is shining into one of the eye pieces? Did you have to look in through the other eye piece, or did you use a camera? Whatever. So, I ultimately threw out Art Ashkin's design, tried to understand the basic principles of how this thing was going to work. Which, by the way, was a wonderful exercise, because that, being thrust on my own to learn that is really how I did learn it for the first time ever. Stymied by Ashkin's diagram, I went back to the drawing board and I really, really bothered to understand how an optical trap works. So, it sounds simple, all you have to do is produce the diffraction limited focus of the laser in the specimen plane of a microscope, and then that trap, that would trap things. But you wanted to do more than that. You also wanted to move that focus around in a 3D volume of your specimen. You wanted to move it left and right and up and down and in and out. And so how would you then take a focus and move it? You need some external optics to do that. It can't be the same optics that are used to focus the microscope because that needs to be on the specimen, and you need to move something relative to the specimen. So, you needed to build external optics that could scan and move a beam. And this had actually all been worked out back in the days when people developed the confocal microscope, which is another Nobel prize-winning invention. And the confocal microscope basically contained all the secrets of how you move a diffraction (inaudible 2:01:52). So, my study of this led me to the confocal microscope. My study of the confocal microscope led me to understanding how I would do this. And I had it all designed. And this was all in a matter of two days, we're talking about here. Tops. In which I went from reading Ashkin's paper to having designed my first optical trap. Except there was a problem. I wanted to buy a laser, I wanted to buy all these lenses, I wanted to buy these dichroics, I wanted to buy all this stuff. And of course, it took a while to get it. So, I ordered literally during my first week at Harvard, Rowland, and the stuff came in, and I started putting it together, and it went together amazingly quickly. I think I had my first trap going within like a day or so. Had all the pieces put together, but there was one problem, which is I didn't have an e. coli specimen to trap. To test this. Why? Because Howard Berg was still moving across the country from Caltech to Harvard. He had only, he'd arrived, but the moving truck which was carrying all the strain collection was still en route from California. And the stuff had only just disembarked at Harvard, and they'd just stuffed the freezer full of these frozen strains, but if I was to get one of those strains, I would not only have to drive over to Harvard, but I'd have to come back, I'd have to culture the strain, wait a couple of days for it to come up, and so forth and so on. So, I used a trick that almost every microscopist knows when you can't find e. coli (laughter). I took a cover slip out and I scraped the front part of my tooth. Now, you would think, if you brush your teeth every morning and every evening, as I do, and you've flossed correctly, as my dentist insists, you'd think if you did that, nothing would happen, but you'd be totally wrong. The surface of your tooth is still not one, but a zoo of perhaps a dozen different bacterial strains. Some of which actually are highly modal. Some of which are long and thin, some of which are short and fat, and a lot of which look a bit like e. coli, but they're not. But they swim around like gang busters. And so, I re-suspended this little white bit of glob that I scraped off my tooth in some buffer, put it under the microscope, and sure enough, I had things swimming around. And the trap worked, and I was able to trap them. And this was fantastic. And I had at the time an external lens which moved around, and the motions of that lens would produce motions in the specimen of the diffraction limited spot. And so, I called this the optical etch a sketch because I had one knob which did left and right, one knob which did up and down, and you could turn them together and you could grab bacteria and you could make it do a square dance by turning the knobs in succession in different directions. And I thought this was the greatest thing of all. And then I was visited shortly thereafter by a guy named Steve Smith, who's a famous neuroscientist. He's at the Allen Brain Institute today in Seattle. He used to be at Stanford, and before that he was at Yale. He was a Howard Hughes investigator. Steve was my old buddy. He came in on a visit and he was astonished that he could not only capture bacterium but by turning the knobs just right, you could write your name with the bacterium under the microscope and record it on video (laughter). So, the optical trap came together, it was a thing of beauty. The next thing to do was to calibrate it and figure out how much force it was generating, and so I spent the next year and a half or so doing some experiments on bacteria, actually, on their flagella filaments. I showed that bacteria filaments are actually attached to the motor itself. Not directly, but through a flexible coupler which acts like a U-joint, so that the filament can be in one direction, but the motor can be pointing out of the cell in a different direction, and it'll communicate power of axis. These work a lot like those little bendy straws you used to have, which had a flexible accordion pleat at the top, and you could bend the straw, but if you turned the bottom of the straw, the upper part would bend, but it would go through 100, or a 90-degree turn. Bacteria have the same thing; it's called the hook. And with the optical trap, we were able to measure the elastic properties of the hook, showing that it would bend in one dimension, but then it would lock up and communicate torque in that modality. So, this was one of the first measurements close to the single-molecule level with an optical trap. Now, the hook is composed of about 250, 260 individual protein filaments, so this wasn't quite a single molecule experiment. But I spent the next year or so trying to show that you could get individual kinesin molecules to hook onto beads. And I did this work in collaboration with Bruce Schnapp, who had been at Woods Hole and had been one of the co-discoverers of kinesin. At that point he'd moved to Boston University, and also with Larry Goldstein, who was a researcher at Harvard, who was also interested in kinesin. And we got together, they supplied the protein, I supplied the optical trap and some of the physics and the analysis, and together we were able not only to get single molecules of kinesin to move, but we were actually able to start to begin to measure the forces, the velocities, and so forth, so we were off and running. And so, it ultimately turned out that kinesin was a great molecule to work with. And the next thing to do after discovering that you could get single molecules to work and that you could measure their forces and that you could measure their forces as a function of velocity, the next thing was to ask, "Well, do they move in steps? Could we measure the individual steps taken by these motors?" It had been long hypothesized since they move on polymer filaments, that they jump from one (inaudible 2:07:26) end of the polymer to the next, which would synthesize the step. It was thought that myosin moved in steps, it was thought that kinesin moved in steps. No one had ever measured these directly. And it was an outstanding question. So, the great step hunt who started, at that point my lab was joined by a grad student from Harvard named Karel Svoboda. Karel is famous in his own rights today. He's at Janelia foreign research campus of Howard Hughes. And he works on two photon confocal microscopy of neurons and has made quite a reputation for himself. At the time, Karel actually joined the biophysics program and was working with Howard Berg, who brought him to meet me at the Rowland Institute. And I got Karel and a postdoc named Christoph Schmidt interested in the problem of how to measure molecular steps. And so that required an addition to the optical trapping apparatus, and that addition was to figure out a way not just to apply forces, and not just a way to move the trap, but a way to measure the exquisitely small displacements that take place within the trap. So, you basically needed a nanometer. You needed a device which was sensitive to really, really tiny displacements. And there are three or four or five different ways of doing this, but at the time I was casting about for a way to do this, and I came across the work of a guy named Winfried Denk, who is today Max Planck director in Munich, and before that in Heidelberg. Denk is the co-inventor, by the way, of the two-photon microscope, with Webb at Cornell, so Denk was a grad student at Cornell. An immensely creative guy, also a good friend for life. And Denk was interested in how we hear at the time. We have these things in our ears called hair cells. The hair cells vibrate because they're driven into vibration by fluid, which is in turn pumped by the bones in our middle ear, right, the hammer and the stapes push on the ear drum that moves fluid, the fluid moves the hair cells, and the hair cells somehow cause or transduce this into an electrical impulse. So, it was thought that when you moved the hair cells a tiny bit, electricity would flow, they must be opening channels of some kind. And Denk wanted to know what fraction of the motion is transduced into an electrical signal. Why? Well, because we can hear so acutely and some organisms can hear even more acutely, that it was thought that we could hear right down to the level of Brownian motion. That the zero-point motion, the Brownian motion, of the hair cell at room temperature was sufficient to actually produce and full of ions, which would be measurable. And if that's true, you should be able to do the following experiment. You should be able to measure that Brownian motion, the exquisitely small amount at the nanometer level, and simultaneously measure the voltage output. And those two signals should be cross-correlated. Right? The more you move, the more voltage you get. And so Denk set about building a displacement meter, because he needed to measure that Brownian motion. And of course, the at the time, this was in I guess it was 1976, that (inaudible 2:10:38) got the Nobel prize for discovery of single channels and the motion of currents through single channels. So, the technology had existed for ten years for measuring the picoamperes of current that flow when channels open up. So, you want to measure, you know, nanometers, piconewtons, and picoamperes. And Denk figured out a way to do this using one of the modalities of a light microscope. Light microscopes were revolutionized, first by the invention of phase contrast, for which Zernike got the Nobel prize in physics, mind you. And later, Nomarski developed what's called differential interference contrast microscopy, or DIC. Which is particularly well-suited to work with video, where you can play with the gain and the contrast, but DIC works by a kind of wavefront shearing using different polarizations and then the waves get recombined and depending on the polarizations, they recombine to give you shades of grey that correspond to tiny differences in optical thickness. But they also will change the shades of grey depending on tiny differences in displacement, provided you're in the right position with respect to where the wavefront shearing is taking place. So, Denk modified a DIC microscope by sending through not parallel light across the whole aperture, which is called curler illumination, he sent it through, in fact, in a tiny diffraction-limited spot. Which is, you know, the best you can do is about the wavelength of light. So, it's a spot about a micron across. And within that spot, you have two beams of orthogonal polarizations, which were slightly split from one another. Split by about a tenth of a wavelength. And there was an object within that diffraction-limited spot which then moved, it would tend to bind as one polarization versus the other. So, you could then tease that apart with quarter wave plate and look in two different channels, at channel A and channel B, and then compute channel A minus B over channel A plus B, you'll get the differential measurement, in other words. And you could actually turn that into a displacement meter. If the object moved a tiny bit, it would favor one polarization versus the other, resulting in a change in the ellipticity of the light that came out, was mostly circulated polarized, but with a little bit of ellipticity. And then by building essentially an ellipsometer, you could measure that tiny, tiny displacement by seeing a change in the overall polarizations of the light that came out. So Denk built this and discovered that, lo and behold, the hair cell in the ear transduces about seventy-five percent of its signal into an electrical signal when it's just being driven by Brownian motion alone. Or put another way, the hair cells in our ears are tweaked to the physical limits of perfection. You can't do much better than that because after-- we're any better than that, all you'd do would be to pick up noise. You wouldn't pick up signal anymore at that point. So, this is the auditory equivalent of a very famous experiment done during World War II, showing that our eyes can pick up single photons. So, and in fact, I've written articles about transduction, pointing out how the different senses, our sense of electroception in sharks, magnetoreception in bees, vision, hearing, taste, are all tweaked near the physical limits. Of course, you have to compute what those physical limits are, and so forth, and so it's very interesting to sidelight. So, when I wasn't doing kinesin research, I was interested in this other stuff. Back to our story, I realized that in many ways, an optical trap was very much like the device that Denk had built. Denk's device used a red laser, used a Hene laser. In fact, it used the same laser that was being used at the time in supermarkets for checkout. Today, of course, we use diode lasers, but back then they had these Hene lasers. And I didn't want to use red light, of course, because it was damaging to a lot of biological specimens. But I realized that, you know, one aspect of his work was it had diffraction-limited spot. I said, "But an optical trap is a diffraction-limited spot, it's just at hideously higher power and it's in the near infrared at around one micron. So, therefore, if I tweaked the optics of my microscope a bit, and I put in these so-called Nomarski prisms, and I send in the light not in one polarization but in two orthogonal polarizations, to that same diffraction-limited spot, I could build what I called an optical trapping interferometer. It was simultaneously an optical trap and an interferometer that would report on displacements down at the nanometer level.
Did you know it had this duality from the beginning, or you discovered this later on?
Absolutely. No, no, no. It wasn't discovery. I was casting about for ways to measure displacements, and one of the ways in the days was to simply image your bead, or whatever it is you're looking at. Image it on a quadrant photodiode. And watch it move from one quadrant to the next. Or image it on an array. A lot of people were using these, you know, linear rays, in 256 little photodiodes in a row and you'd measure it. Of course, the array is pixelated. The quad photodiode is an analog thing, but it has a disadvantage, which is the following, that if your image is cast on with your photodiode itself, if the photodiode itself shakes due to vibration, that's indistinguishable from your object moving due to vibration or due to its actual, secular motion. So, you have this problem with noise, which is that on a quad photodiode, any movement of the detection arm of your microscope was indistinguishable from the displacements you were trying to measure. And if you're trying to get down to the nanometer, even today, the picometer, that was going to be a real problem. So, I was casting about for ways that were independent of the detection arm of the microscope. And it turns out Denk's interferometer that he'd built with Webb for looking at hair cell motions was in fact independent of vibrations of the detection arm. And depended only on motions within the spot itself. Now, I also realized that if it was an optical trap and you had an object in the trap, if the trap wasn't particularly stable, let's suppose the trap moved a little bit left and right, if it carried the object with it, then you wouldn't get a signal. The signal only depended on the motion of the object relative to the trap. Not in absolute space. So, you were immune to two kinds of noise. You're immune to the trap itself wandering a little bit. We're talking fractions of a micron, but still, that's a problem when you're trying to measure nanometers. We were immune to the vibrations of the detection arm. So, I realized that Denk's device could be adapted, and that instead of using a detection laser, I could simply use my optical trapping laser and recycle the light. I would use it once for the trap, and then I'd capture that same light as it emerged through the condenser side of the microscope and send it off to my detection arm, which hadn't been done before. So, we built an optical trapping interferometer in, I think it was '91. 1991. And within a year, we had measurements of kinesin and we were able to see the individual steps that it took. And the steps turned out to measure at eight nanometers. And they were precisely the same distance as the subunits of tubulin are from one to the next along the microtubules. So, it's as if it were walking down the sidewalk stepping from stone to stone. And we were- so, that was the first measurement of kinesin steps. Since that time, people have looked for sub-steps in the motion, people have measured the timing of the steps. They turn out to be distributed in interesting ways. At low kinesin concentrations, you can see single molecules stepping, and the steps are exponentially distributed, so they step at random times. You can correlate the different motions of the molecule through the stepping cycle with its stepping motion by using different ATP analogs. Which cause it to stall out in different parts of the cycle. There are lots of experiments, hundreds of experiments that have been done on kinesin since that time. But they all rely on being able to see these steps. It turns out that under some conditions, the left step and the right step, so to speak, take different amounts of time. We can get kinesin to limp, so it takes a short step, or a short duration step and a longer duration step, in strict alternation. And that argues that the two heads of kinesin, kinesin is a two headed beast, the two steps of kinesin would actually strictly alternate as it moves forward. So, this alternation in stepping was something that came out of that work. The proof that kinesin could work in the single molecule level came out of that work. The force velocity curve of kinesin came out of that work. And a number of experiments since that time. Kinesin is the founding member of a superfamily of proteins. There are perhaps fourteen different classes of kinesin. And in any cell of your body, there are maybe half a dozen different kinds of kinesin molecules which are being expressed. And they carry out different tasks in the cell. Some transport vesicles, some move chromosomes, some more mitochondria. So, these motors are harnessed for different tasks at different times in your body. But it's been possible to look at different classes of kinesin, which have slightly different mechanical properties. They spend different amounts of time in different parts of the cycle. They produce different stall forces. They move at different speeds. So, all this has been enabled by this technology. A few years later, we were able to get rid of the optical trapping interferometer and use a simpler technology, which is that quadrant photodiode I was mentioning before. Where you have the image of the bead, or actually the bead, cast on the quadrant photodion, and now as it moves, it adds more signal to one quadrant or the other, or subtracts from another. But we were able to get around the problem of the vibration of the detection arm by a clever optical trick which was suggested by a postdoc of mine named Cune Fisher, from Holland. So Cune got excited about optical traps and built one of the very first ones when he was in grad school at the University of Amsterdam. And he'd brought me to Amsterdam to serve on his thesis committee for his thesis defense. So, I got to meet him there. And I was very impressed, and I picked him up immediately as a postdoc, and he came to work for me first at the Rowland Institute, and later at Princeton, and Cune had the bright idea that instead of looking at an image of the photo, of the bead on the photodiode, instead, we set up the photodiode so it's optically looking at the back aperture of the condenser of the microscope. When it's looking, or in focus, at that point, it's not looking at an image of the bead, it's looking at an image of the Fourier transform of the bead. So, the back aperture of a lens, from optics, basically contains that transform. It's not perfect, it depends on, you know, on parallel rays and things like that, but to a very good approximation, the back aperture of a microscope is looking at the Fourier transform of the object. And it turns out that movement of the object in real space corresponds to a change in phase in the Fourier transform. But as long as you pick up the whole transform... As long as, in other words, your detector is bigger than the size of that thing that you're imaging, then it doesn't matter if your detector moves a little bit left and right, or up and down. You could still measure it and the signal you get is independent of that. The transform only changes when the object moves with respect to the trap. So that achieves the desired goal, which is that vibrations of the detector are no longer, give you a signal. So that came along second as a way of detecting things. And to this day, either using a quad photodiode or using what's called a PSD, which is a position sensitive detector. It's another silicon or germanium device that can allow detection of position. By using one or the other of those, you can make nanoscale measurements of objects in optical traps and you can make those measurements incredibly accurately. We got to the point where we could measure the motion of the bead to within an angstrom and make that measurement of order fifty times a second. So of course, a physicist will talk about the bandwidth of the measurement. It's not sensible to talk simply about the measurement what, you know, because you could take a noisy measurement, which is zero mean, and you can measure it many, many times over and average out the noise, right? So, the real question is, well how fast can you do it with a given precision? And so, what you really are asking for is the power spectrum of the device. So I'm fast-forwarding now to many years later, because shortly after the kinesin steps were discovered, one of my colleagues went to me and said, "Well, if you can do that, can you measure the steps taken by a molecule moving on DNA? As it goes from base to base?" And now those steps are about twenty, twenty-five times smaller than the kinesin steps. And measuring at eight nanometers was the state of the art then. I mean, that was, you know, that was the cat's whiskers, and I didn't think you could do much better than that. So, I sat down and did a back of the envelope calculation, which was based on, well, I knew what the stiffness of the spring, the optical trap essentially acts like a spring. I knew the optical spring stiffness. I knew the kinds of displacements we were looking at. I knew the temperature, and so I knew what KT was. I could figure out what the Brownian noise contribution would be. And I asked myself, if I made the trap stiffer, there are limits to how stiff you can make it. You can increase the light level, but if you increase it too much, eventually the optical trap becomes a problem for opticution. It burns up whatever you're looking at. And the other problem, of course, it becomes so stiff that if in the one step, you exceed the stall force of the device, it won't move. So, kinesin, there's a stall force, sixty-eight piconewtons, right? So, if the force by the trap increases by more than sixty-eight piconewtons within a single step, it won't move anywhere. So, there are limits to how much force you can produce. There are limits to how much light you can enter. There are limits to the stiffness. There are limits, well, the temperature is what it is. And I convinced myself, based on a back of the envelope calculation, that it would not be possible to measure the motions at the angstrom level. I was thoroughly convinced of this. Turns out I was doing the wrong calculation. The reason I was doing the wrong calculation is I was doing the calculation for a stationary optical trap. A few years later, we invented a different device, which is the optical force clamp. An optical force clamp is an optical trap that changes in such a way that the force on an object that it's trapping is constant, invariant. It doesn't change over time. Now one way to do this was with a trap follower. As soon as your object starts to move, you move the trap along with it. Always keeping a certain distance away from it. So that's like stretching a spring to a certain amount, and when the object moves, you keep the exact same stretch in the spring by moving the trap accordingly. There's a problem with that, which is you can only know that the object's moved by measuring its displacement. That takes a certain amount of time. Because it's a noisy signal. And you have to average over a few cycles, maybe, to figure out that it's moved a little bit. Then you have to have a feedback loop, which moves your trap. Then of course you have to move the trap. How are you going to move it quickly enough? We use these things called acousto-optic deflectors, which can move very fast but not infinitely fast. So, you move the trap along, but you have the loop closure time of that feedback cycle, which limits how fast you can essentially work a force clamp. And for some of these things, that was too slow. But the force clamp has the advantage that all these stiffness terms that I was talking about in the calculation that I mentioned earlier just drop out of the problem. And it turns out that the amount of motion that you have to impart to your trap to keep things at the same force is exactly the amount that the thing steps. And there's no limit in principle to how low you can go. You're no longer limited by the kinds of things that you were limited to before. And so, it would be possible, at least on paper, to measure angstroms with that. And the problem with it was loop closure time. So fast forward to the 2000s, when we solved that problem finally too. And the way that problem was solved was the only Phys Rev letters paper I have ever published (laughter). The way you solve that problem is with something called a passive force clamp. So, it turns out that optical trap, if you think about it, acts like a potential well. Any potential well sufficiently close to the bottom, it looks like a parabola. So, you're sitting in this harmonic potential, a parabola, and almost all optical- that means, of course, that the thing is acting like a spring, because the derivative of a parabola is a straight line, and that's Hook's law. And that's why the displacement goes up linearly with the- the force goes up linearly with the displacement as you move an object out of the trap. And there comes a time when you get to the edge of the trap, where eventually you can just pull the thing out of the trap. And at a large distance, there's no force at all, because you're out of the trap and gone. So, this parabola comes up, but it must ultimately go through a crest and then come down and the potential flattens completely, it goes to zero, and the force goes- I'm sorry, I'm saying this badly. The parabola comes up and the potential goes to a constant. There, I'm setting it right now. And you have flat energy. And the force, which is the derivative of that, goes up and then it goes back down to zero again. So, if you're outside of the trap, there's zero force. So that, by continuity, what that means is that somewhere near the limb of the trap, out towards the edge, the force must be growing then stopping its growth all together, going flat, and then dropping back down to zero again. That means the force undergoes a maximum. Well, anything sufficiently close to a maximum is a flat surface. So, if you could somehow take your trap bead and move it out to where that potential is- I'm sorry, where that force is flat, what you discover is that it's got a force on it. But for a small displacement, there's no change in that force. Because remember, the force is flat. So, we move a little bit left and right, no change in force. But that's what a force clamp does. A force clamp is designed so that when you move an object, the force stays constant. So, an optical trap itself acts like a force clamp over a very small region at the very limb of the trap. And this is what's called a passive force clamp. Now, the beauty of this of course is it doesn't depend on feedback at all. It in sense works infinitely fast, or more accurately, it works at the speed of light. And so, compared to anything we can measure, the force is instantaneously constant for motions of the bead, and invariant. This is just what you want. The problem with it, insofar as there's a problem of course, is you might imagine that force goes up and comes back down, and the region where it's peaked is very narrow. Well, one man's narrow is another man's desert of flatness. And the reason for that is, of course, it's changing on the scale of the wavelength of light. And so out in that flat region, it's maybe a quarter, a half, or a third of the wavelength of light, over which it's flattening it out. But the wavelength of light is of order 500 nanometers. And so, we only need it to be flat over a few nanometers. Over even angstroms, in some cases. So, it turns out that that provided ample room for us to do our work. Out in this flat zone of the optical trap. And so, the passive force clamp was invented. And we would pull our bead out into that part of the trap using double tweezers. In this case, we had tweezers on either side of the molecule, and so we could use one tweezers to pull the bead into this flat zone, where it was passively clamped, and then if a motor were attached to that, then moved even down to the angstrom level, we could see those displacements. So, this led in the 2000s to being able to actually watch a single molecule of RNA preliminaries take steps along DNA as it transcribed the gene. And the steps it took were 3.4 angstroms, precisely the distance that Watson and Crick had derived in their paper of 1953, I think? '52, '53. In the famous paper published in Nature. This was important. In a lot of ways, not only was it a crowning achievement for measuring small displacements of optical traps, but it also ruled out one of the mechanisms of motion that had been proposed. A guy named Mike Chamberlain in Berkeley had argued for a so-called "dis-continuous" elongation model of RNA-P, in which the steps would be jumps corresponding to a loop of DNA that it would take in and transcribe and then release. Another loop, take in, transcribe, release. And those loops would be of variable size. Turns out nothing of the kind takes place. The molecule literally moves from one base to the next. Not only that but, well, you can measure again the force velocity relationship. And the steepness of that curve told us something about the way in which the molecule spent time in the post-translocated state versus the pre-translocated state, without getting too technical. It told us a lot about the life cycle, as it were, or the duty cycle of RNA preliminaries as it synthesizes RNA. So we learned a lot from those experiments. It wasn't just being able to measure a small displacement. It was more about trying to parse again more information out about the molecular mechanism by which RNA-P works. And there have been lots of papers since that time on the effect of co-factors on this, on the effects of different structures in the DNA itself. Different bases. The preliminaries have a very complicated behavior. It can back up, it can arrest, it can pause, it can terminate. And we've had a slew of papers on each one of these phases of the activity of RNA preliminaries. All based on this technology, being able to measure its displacement with angstrom level sensitivity in real time at the single molecule level.
Wow (laughter). We're all over the place in terms of, I want- just in terms of the narrative, to get to your next- when do you know that it's time to leave Rowland and to sort of enter, you know, back into traditional academia?
So, there's a bittersweet story associated with that. While I was still at the Rowland Institute, Edwin Land, who was increasingly in poor health, would start coming in less and less, and then finally he was bedridden on his last. And he passed away. There was a seat change at the Rowland Institute after that. His son-in-law, the one who was rowing for Harvard and fancied himself sort of a gentleman scientist, he'd retired and raised Morgan horses on an estate in New Hampshire. But he would come in once a week to the Rowland Institute and try to run things. And it worked that way for a little while. For reasons unknown to me, Howard Berg was not made the next director of the Rowland Institute. So, the direction-
He wanted that? As far as you knew, he wanted that title?
Absolutely wanted that title. Absolutely, in fact, he'd come to the Rowland Institute with the working assumption that he was, you know, being groomed for the directorship. And of course, he had a lab at Harvard as well that he was maintaining, and so he had something to fall back on, so to speak. I probably shouldn't phrase it as "falling back on it" (laughter) because most people aspire their entire lives to have something like that. But he was able to maintain the lab at Harvard and was doing very well. They hadn't cut off his allowance at the Rowland Institute, so he still maintained an effort there. But the directorship just never transpired. Also, there were a few people at the Rowland Institute who were really not very productive. Berg and I, of course, were very productive. There was another group that was run by a guy named Dongmin Chen, and his mentor Jene Golovchenko at Harvard, which had built a scanning tunneling microscope and were doing great things with that. There was a woman, Lene Hau who is now a professor at Harvard. And Lene, she became famous for slowing down the speed of light, first to the speed of a bicycle, and today it can be stopped nearly altogether in the right refractive index and with the right optics and the right medium. Lene Hau did the first experiments there that slowed light. So, we had some of the first experiments of silicon seven by seven viewed at the single molecule level, at the surface of these. We have Lana Howe's experiments, we have our experiments, so great science was coming out of the Rowland Institute, but there were also a bunch of ne'er-do-wells that weren't doing very much, and it was hoped that they would replace these individuals with people who would be more productive and that really didn't come to pass. And everyone was uncertain at that point because the son-in-law didn't seem to be totally invested in running the Rowland Institute. Scarcely paid attention to the day-to-day activities. Was unwilling or unable to confront any of the lingering issues. And right around then, I received a job offer, unsolicited job offer, from Princeton University.
Sounds like it was great timing for you, also.
Oh, it was great timing. You know, almost everything I'd done at the Rowland Institute had turned to gold (laughter). I, you know, they say chance favors the prepared mind. I'm not sure how prepared my mind was, I just got very, very lucky. I worked very hard, but I got very, very lucky. And all these things that I wanted to have happen when I was a postdoc working on myosin. The dream experiment of steps that I'd thought about back in grad school, all of a sudden it came to fruition. So, the work, at that point, of course there aren't any preliminary steps, hadn't been seen. Those wouldn't be seen until many years later when I was at Stanford. But while I was still at Rowland Institute, the kinesin steps had been seen, and these were very important and to this day, it's my, aside from reviews, that's my most-cited paper. There's over 1000 or maybe perhaps 2000 citations to that paper at this point. Which, for biophysics, which is an obscure little field, is a lot.
So, the steps of kinesin were a really big thing, and what really sweetened the pot for this for Princeton was that they were making me an offer with tenure. And here I was in essentially what amounted to a glorified postdoc. I'd never been an assistant professor. And in fact, hadn't even spent my five or six years yet as an assistant professor. And here I was, being offered a tenure job at Princeton. Sounded awfully good to me.
On the other hand- and one of the reasons I got very, again, they say, you know, you get lucky. I got lucky because purely out of, I don't know, a personal interest, I had been teaching a class at Harvard in sensory transduction, which is this other theme that we were talking about before. And the reason I was teaching the class at Harvard in sensory transduction harks back to this grad school experience, I told you. Where we invented a course of our own in bioenergetics and taught it. And I thought it was just cool that students could teach their own classes, if they got inspired enough. And so I was teaching this course at Harvard, sort of to keep my oar in the water, but when it came time to get, for the tenure case to go forward at Princeton, they wanted to know about all my teaching experience. And if I had just been at the Rowland Institute, I would have never been able to get tenure at Princeton. And instead, I got really lucky. And the other aspect of being really lucky is that Harvard had something called "Q guide" which was undergraduate evaluations. And I got a really good score on the Q guide. The only person in physics who did better than me was Nicholas Bloomerman, who had a course in quantum mechanics. But I had the second-highest Q guide score, so I was kvelling [being proud] about that (laughter). So, this got sent off to Princeton, and they approved the tenure job. So then came the big decision point for me. I wasn't all that keen on going to Princeton, because look at the deal I had. I had no classes to teach, no grants to write, no committees to sit on, and most important of all, I didn't have to worry about the funding. Anything I wanted; I could just tell them to buy.
And was your position, did you have a level of job security that as far as you were concerned was equal to tenure?
Well, that was the sticking point. So, you'd put your finger on it instantly. The problem was that because, what had been understood, although never written down in any contract form, was that everybody at the Rowland Institute had lifelong job security. But clearly, that was not the case, because at this point one or two people had been let go for basically not doing anything. And it wasn't clear to me that there was any direct correlation between how well you did and whether you stayed or not. And whether there was anything resembling tenure or not. So, I finally- it was also not clear on what basis, you know, raises and various types of promotion, would take place, because this was neither industry nor was it academia. It was this unknown thing which ran according to its own rules. And so, I finally got an opportunity to have a sit-down with the director, the son-in-law of Land, whose name was Phil Dubois, du-bois, but pronounced du-boys. And Phil, I sat down with him, and I said, "Look, I'll be frank about this. I've got a job offer from Princeton, but my inclination is to stay here in Boston." My wife and I have some groups here. I had all these collaborations in place. I had a steady supply of grad students coming from Harvard. Hard to beat. The work was sufficiently high-profile that postdocs were writing me letters and asking if they could work with me. So even though to Rowland Institute was somewhat isolated for the reasons we've already talked about, it looked like I had a really good deal going. And so, I said all I really need to know is, do I have any kind of job security there? Can you commit to what's going to happen in the next two or three years? Are you planning to make Berg the director? Are you planning to give something like tenure to the people here who perform up to some standard, which you can establish? And so forth. I-
So, obviously, you were asking him questions that were of much greater import than just your own career? Because he would have to make sort of systematic changes to the entire employment structure based on what you were asking.
Once again, you've put your finger on the crux of the matter. That was precisely it. And it turns out, the bottom line was he was unprepared to answer any of those questions. He was unprepared, perhaps because as you perhaps ascertained, he was unprepared because he himself had not decided what the future of the thing was going to be. He himself had not decided what was good science or bad science. He himself had not decided what to do about Berg. And so forth.
Steve, and you can edit this out of the transcript if you want and give me an unvarnished opinion now, but was your sense that his position was simply a family connection and he was out of his depth both scientifically and administratively?
Okay. It sounded like that. I wanted to get your answer, we can deal with that later, but you know.
You may keep it in the transcript.
So, fast forward a few years, I of course did move to Princeton, took up a tenured position in the department of molecular biology, with a joint appointment in the Princeton Materials Institute, which was a new institute which was involved in some physics-y things.
Which was probably interdisciplinary at birth?
Interdisciplinary at birth, but there's more to it than that and we'll get to it in a moment. But after a few years, it turns out Phil Dubois decides to step down from the day-to-day management of the Rowland Institute, which he never had a heart in anyway. He appointed one of the internal people named Mike Burns to take care of the day-to-day operations as director. Mike Burns is a good scientist, but not a manager, and eventually the family decided to unburden themselves of the Rowland Institute, and shopped it around, and basically gave it to Harvard University. So, the Rowland Institute that exists today, it is now run by Harvard University. It's a very different place. I mean, architecturally it's the same, it's a beautiful place, mind you, but it's run by totally different rules and in a totally different format. And I was there for a heyday, a flame that burned brightly but briefly in which some fabulous science happened and nothing like that has happened since.
So, the professors there now are Harvard professors?
Yeah, they also- well, they populated with a lot of postdocs, they're Rowland Fellows. They have a Fellows program now. And they bring in postdocs, these kinds of super postdocs. Kind of along the lines of what I was when I was at Rowland Institute. But under very different rules and conditions. They don't have unlimited budgets; they are not unbounded by the things that they could do. They're for finite term, not infinite term. Lab space is at a premium. And the person who runs it reports to Harvard. It's a very different place. So, the Rowland Institute of today is not the Rowland Institute of its heyday while Land was still alive. So, I was able to experience it in its last years as the personal playground of Edwin Land. And it was quite the place. And as I say, a lot of good science came out of it. There was the scanning tunneling microscope work of Dongmin Chen and Jene Golovchenko. There was some work on optical binding forces. Lene Hau and Mike Burns, I should add. Lene Hau did, with Golovchenko, did a lot of the work on slowing light, also with Mike Burns. So, there was some good stuff coming out. But there was also some weird stuff. There was one computer guy who was just basically weird. You could probably cut that out of the transcript. There were other people there who were far, far less productive. In many ways, I used to call it Lotus Land, you know, as in the Odyssey? There is an advantage and a disadvantage to being in a place where everything you could ever want is done for you. The advantage is you can do anything you want. The disadvantage is, you're also free to do nothing. And there's something a little bit terrifying about having constraints removed. And I know it sounds silly, you know. Most people are pushing against the constraints. They only can wish that they could have an extra $10,000 to buy that laser or only wish that I could do this. And if I could, everything would be so much better. When push comes to shove and all that happens, the fact of the matter is, you're now limited by your own imagination and your own ability form collaborations, and your own ability to come up with bright ideas. And that can be flat-out terrifying. And so, the Rowland Institute was good for some people and bad for others. And I credit Howard Berg again for this. I went through a period in my life back in grad school when I was just goofing off and not doing anything. And it was Howard Berg's letter to me that caused this space transformation in which I suddenly got buckled down and did some work and discovered that if you did a little bit of work, that would lead to more work, and that would lead to more work, and then finally you'd have something to show for it. This is very true in graduate school. You know, the first extra hour you spend, nothing gets done, and then another extra hour, a little bit gets done. And it's totally non-linear. After a certain point, all of a sudden, things take off and results happen. But productivity is not related in any simple way to the amount of effort you put in. And particularly those extra hours. Those extra hours only paid off usually at the very end. In a very funny way. But I had a taste of that in graduate school, and I realized that if I worked hard enough, maybe I'd get lucky, or maybe my luck would come from my activity, but in any case, something would happen. And here around me I had all this fabulous inspiration. I had the work of Edwin Land for me, I had the work of Art Ashkin, who invented the optical trap. I had the work of Winfried Denk, who invented this interferometer. I had Howard Berg, who has been a one-man institute of science, of bacterial chemotaxis and motility. And so around me was all this inspiration. And the last one, who I haven't even talked about yet, was Ed Purcell. Berg has a long-standing relationship with Purcell. And introduced me to him. And I got involved with him and I had myself had an instant relationship with Mark Schnitzer, who had then was an undergraduate at Harvard. He was a Goldwater, he won the Goldwater Award, which for I guess, best young physicist. Mark was so bright that he had a solo author paper in Phys Rev E as an undergraduate at Harvard. With some math that I couldn't even approach, so hat's off to Mark. But Mark worked for me on optical trapping, and eventually became my graduate student when I moved to Princeton. And I worked with Howard, and Howard worked with Ed Purcell. And there's one paper that I'm so proud of, it's the four-generation paper. It's a paper authored by Ed Purcell, Howard Berg, myself, and Mark Schnitzer. And each one mentored the next. And it's a wonderful paper examining some aspects of bacterial chemotaxis. Purcell, of course, his interests ranged over everything you can imagine, and he had one of the earliest Macintosh computers, you know, the little baby Macs. Which had, it interpreted BASIC in it. And he could do more to simulate motion with an interpreted BASIC on a Mac than most people could do with supercomputers. And the way he was able to do this is he would do these back of the envelope calculations which were just this fabulous complexity of bacterial motion, to just a few simple equations which he'd simulate in real time on the Mac. So, he was able to take what was in principle a really hard computer problem, and then turn it into a really deep mathematical problem. But so, you know, this was the kind of inspiration I had around me when I was at Harvard. I had people like Ed Purcell. I had Bill Press, of Numerical Recipes fame, who at the time was at the Center for Astrophysics. He's since moved to Texas. And of course, Berg himself. So around me where these brilliant minds and it was hard to leave the Rowland Institute. It was hard because I was, that was the point when I moved to Princeton, is the point when I was really for the first time in my life starting out totally independently. And in some ways, it was terrifying, and in some ways it was rewarding. But I knew I would have to write a grant, and I have to get it funded, and I knew that I would have to recruit students.
What about building a lab? Were they doing that for you, or you had to do that also?
Yeah. Yeah, not only did they do that, well they built a lab, but they were cheapskates, so the other downside of Princeton is they were offering me prestige, but they weren't offering me a lot of money. Neither did they offer me a large salary, nor did they offer me generous support to start up the lab. I discovered that a good many of my former students when they graduated were getting two to ten times as much money to start up their labs as I did (laughter). And this was only three or four years later, so it was not inflationary dollars that accounted for the difference. So, they really gave me a lowball offer. On the other hand, I already had a lot of equipment at the Rowland Institute, and I was able to broker a deal to bring a lot of the equipment with me to Princeton. Had I not been able to do that, I'm quite sure I wouldn't have been able to hit the ground running there. Also, I was able to get students like Mark Schnitzer, who I knew at Harvard, he became my student at Princeton. And I told you about Cune Fisher, who was in Holland. Another student who joined me there was Tom Perkins, who's today the director of JILA at University of Colorado. And Tom Perkins actually did his undergraduate work at Stanford working with Steve Chew. And Tom had gotten involved in optical traps. But he knew me because his father was in JASON, and I was in JASON, and I knew his father from my summer work in La Jolla. And so, Tom came down to visit and I took him out to a fancy seafood restaurant in La Jolla and weaved my web and convinced him to come postdoc with me. Which he did, and he did a great job. So, I attribute a huge fraction of my success to these various other people that, you know, came to me partly through the connections, partly through friendships, partly through osmosis. And I mean, no lab is, I think, is really built without lots and lots of people helping out. And, you know, insofar as I've been successful, it's because I've had some just amazing people walk through my group at the time. I mean, I'm very proud of the fact that three of my former students today are on the faculty at Stanford. And, you know, also on the faculties of other, you know, great universities, but there may be only one or two other professors at Stanford who can make the claim that their students are, you know, so well-employed. And of course, I don't take credit for that directly. These people got there by virtue of their own brilliance, their own hard work, their own accomplishments.
But they are probably beneficiaries of your mentorship and the way that you had two incredible mentors.
Yeah, but it's a two-way street, yes. I mean yes to all that, but yes to the fact that I benefitted from them, and there's a kind of synergism that develops. And I was talking before about how, you know, a little bit of work doesn't get you anywhere, and it becomes non-linear. I think the same is true for collaborations. A little bit of collaboration, you get somewhere. A little bit more, maybe you get some more. But if this ramifies, if this really gets into it, you get to the point where you each spur each other on to a level that you wouldn't have without the other. And I think I've been really inspired and, in many ways, I was challenged by my grad students and postdocs to do better than I would have otherwise. So, I'm really grateful for that. And as I say, partly it's you get lucky, and success breeds success, it's like rolling a snowball down a hill. And getting the snowball going is one thing, but once it gets going, damn, it's amazing to see what can happen.
Looking back, do you think, was your intention to always move on from Princeton? Did you think you were going to make a career there and then Stanford sort of just happened for you?
No. I have another story that goes with that. It was not my intention to move on from Princeton. I would have been happy there. You know, you're within spitting distance of New York City and all that it has to offer. You're at one of the top universities with arguably one of the best physics departments anywhere. I had great colleagues and so forth. But what I really wanted to do was see biophysics grow and prosper at Princeton. And that meant bringing in some physicists with those kinds of interests into the physics department. And I actually had a couple of friends in the area who were working, for example, at Bell Labs. David Tank. Or at the NEC Institute, which was founded by NEC and inspired in some ways by Bell Labs and in some ways by the Rowland Institute. Where a guy named Bill Bialek was working. So, there was Bill Bialek there, and David Tank, and others. And I wanted to help bring them into Princeton. And I wanted them to hire some junior faculty. And so, for a few years there, we held several searches in the physics department for junior faculty. And it was very frustrating for me, because someone would come in. A few of them gave just terrific lectures. And then the time would come to consider whether to give them a job offer, you know. And the way Princeton would do this is all the faculty would assemble around a large table, and instead of discussing the candidate in some kind of dialogue, they would literally go around the table one person after another, and each would have a chance to speak with respect to the candidate. And by and large, there were very few interruptions and very few questions. So, it would just be an individual speaking and then the next, the next. So, what would typically happen is the first individual would say, "Well, I went to the seminar and I'm not a biophysicist, but I thought it was really interesting." The next person would say, "Well not only was it interesting, but I got a chance to interview the person, and we found we had a lot of talk about." The next person would say, "We not only have a lot to talk about, I was amazed how much physics this person knew. I think they could actually teach our quantum mechanics course, not just some biophysics thing." The next one would say, "Well not only that, but we got to talking about some experiments I'm doing, and actually some of the technology that person uses could translate into my own work. We already have in mind a collaboration we might do if this person were to come here." And this would sound better and better as it goes around the table. Then you'd finally get to some éminence grise at the end of the table, who would get up and say, "Well you know this is all good and well, but it's not physics." And that would kill it. Absolutely kill it. The Princeton physics department paralyzed itself for a period not of months but years. Convinced that biophysics was not a branch of physics. They had people like Stan Leibler there who were trying to convince them that maybe there was such a thing as "biological" physics. Or maybe it's physical biology. But is biological physics or physical biology in any way different from biophysics? Well, they were using this just to distinguish themselves from the people in the Biophysical Society, which they were not so fond of, who worked on things like protein structure. And while it's worthwhile making a distinction between structural biologists, crystallographers, and other people like, and biophysicists, while it's worth making that distinction, the kinds of distinctions they were trying to make where, in my mind, not meaningful and certainly not helpful to the enterprise.
And possibly, to state the obvious, perhaps this is simply, you know, a statement more about the culture of the physics department than it is about the maturity of the field of biophysics.
Absolutely. Once again, David, you have put your finger on it. And not only is that true, but it's also true that biophysics is one of the most quintessentially inter-disciplinary sciences you can mention. You need to know two vast fields and be able to work at their intersection. And so, to try to draw little perimeters around this stuff, works in the wrong way. To try to do biophysics. You know, real biophysicists don't care about these boundaries. The last thing they ought to be doing is trying to define them with new words. So, I think it was done more for marketing than anything else. But you still find, if you interview people, you'll find lots of people who claim to be doing biological physics and somehow want to tell you this is different from biophysics. Now, as a past president of the Biophysical Society, I can tell you that this is a distinction without a difference.
But anyway, back to our story. I got increasingly frustrated that Princeton physics in particular seemed utterly unable to do this. There was another thing that frustrated me, which is that for a number of years, I wanted to be put up for a Howard Hughes professorship. And Howard Hughes professorships were gold. They would give you a ridiculous amount of money, you wouldn't have to write grants. You were relieved of a certain amount of teaching duties. You got an administrative assistant who was paid for by the Howard Hughes Foundation, who worked exclusively for you. They tended to have large labs and were extremely well-funded. It was the cat's meow. But this was all funded by the will of Howard Hughes, and by the Howard Hughes Medical Institute, which thanks to a change in law in Congress, was forced to divest itself of a certain amount of the fortune that it squandered. It was originally a tax shelter for Hughes, so he wouldn't spend money. And then they were forced by Congress into having to spend something like five percent per annum. And that five percent turned them into the single largest benefactor of the biomedical sciences in the world. So, I wanted to be a Howard Hughes professor, and two or three of my, well, let's call them "competitors" in the single molecule biophysics field, already had these Howard Hughes professorships. But there was a problem, which is that in the early days of Howard Hughes, they gave them out to anybody who provided they made the grade. But then they started restricting the number of applicants. So, instead of just applying on your own, your university had to apply for you. And then universities were restricted to only putting in the names of first one then two then three applicants, but depending on the university, but you had to win the sweepstakes in your own university before your name could even be forwarded to the Howard Hughes, otherwise they wouldn't consider you. So, in a place like Princeton or a place like Stanford, your main competition is not the other people, it's the people in your own university who are ahead of you in line and want that Howard Hughes nomination. And in the early days of this, the nomination alone was, if you were at the top ten university, was usually sufficiently good to get it. And it's changed over time. And the way, and they kept revising the rules. But at the time when I wanted to do this, Howard Hughes had a sort of, the arrangement I just described. However, in the year that I was to apply for it, Howard Hughes said that they would prefer candidates who were women. Now, this was not an absolute restriction, but it was sort of the year of the woman for these applicants. So, I found myself on the wrong side of the gender divide on that. And Stanford decided to go for it with a woman candidate instead of me. So, I was sort of first in line, but I got pushed to second in the line. But the tragic irony of this is the woman candidate put forward ultimately did not get that Howard Hughes professorship. Meanwhile, Ron Vale, who was one of the co-discoverers of kinesin, you might remember, who at this point was at UCSF, also wanted to get a Howard Hughes professorship. And somehow convinced his university to put his name forward, even though they were looking for women that year. And he did get it. So, I found myself in a situation where I didn't get the Howard Hughes and then that competitor, as it were, one of my competitors did. So that looked tough. So, Stanford came calling and told me that they were interested, and what I liked about their offer was twofold. One was that I would be jointly in both biology and physics, and since I've always had a leg in both places, that was great. They were going to put my lab in the biology department, which is fabulous, since most of my students are physicists but they need access to centrifuges and autoclaves and cold rooms and gel apparatus and the kinds of things, the tools of biology. And if things didn't work, they could just walk down the hall and find somebody to help them. Students working in the physics department, but under those conditions, would be hard-pressed to move forward. So, I wanted a lab in biology, but I wanted a main appointment in physics, or applied physics, which is the department I'm in at Stanford. So, I could recruit students from the physics side and then train them on the biology side. So, Stanford was offering exactly what I wanted.
But they got it, obviously. There was no issue like at Princeton about is biophysics a real thing. There was none of that?
They totally got it. And here's the irony: after I left Princeton, kind of in a huff because of their failure to promote biophysics, you know, because of their failure to promote me, they founded the Lewis-Sigler Institute, which is for biophysics. They hired Dave Tank from Bell Labs, who's on the faculty there. And they hired Bill Bialek from the NEC Institute, who's now on the faculty there.
Steven, could I just interject here? Because there's one thing that's curious to me. I mean, the mid-nineties, it's like the human genome project is going on, NIH is doubling in budget. Is Princeton really that blind to national trends that are going on and to see that, you know, so much of the future is in biophysics? I'm having trouble understanding that.
Well, I think the Princeton physics department is rather parochial. And my view, these are not decisions that are being made by deans or presidents or people charged with a broader view of the sciences. These are decisions being made at the departmental level by, you know, journeyman physicists. And with no experience of biophysics whatsoever. So, I mean, it's really hard to nucleate something when you haven't got an example of it in the department. And they did get Stan Leibler there, but then Stan Leibler eventually left Princeton around the same time, actually before me, for Rockefeller University. Partly because Rockefeller promised to never have to write a grant again as long as he lived. He was also entertaining an offer from EMBL and Heidelberg. And so, in fact, Leibler entertained lots of outside offers when he was there. So, I'm not sure he ever-- I mean, I can't speak for him. I'm not sure he ever really resonated deeply with the physics department there. And there's Bob Austin, who does do biophysics who's in the physics department there, although Bob is from the school of thought of biological physics. Bob, I think worked with Hans Frauenfelder in his days at Illinois, and Bob's a member of the National Academy. A good scientist. But I don't think he had the ear of his colleagues. I don't think there was a lot of sympathy for this. But I guess, I can't say that it's because I left, but you know, after I left, I think there was a change in attitudes. Maybe spurred by the fact that Leibler left and I left and there was a sense that things were going to happen. It's possible. But I wasn't there for the discussion, and therefore can't speak to it. But I can say is that all the motion towards the Sigler Institute and biophysics support happened after I left. And had that happened before I left, I think I might have stayed at Princeton rather than gone to Stanford. Stanford, by the way, also lured me with the promise of a Howard Hughes nomination, which never came to pass either. And furthermore, by the time the next round of acceptances came up, I had aged out and they considered me under their revised new rules too old to apply for Howard Hughes. Now you can apply for Howard Hughes without your university sponsor you. But that's not possible for me either.
Okay, so. Paolo Alto, here you go.
Paolo Alto, here I come. So, it was 1999. So, I was at Princeton from '94 to '99. With some regret, I said goodbye to Princeton. They did promote me to associate professor, although that was, didn't come with very much of a raise. The other reason that Stanford was willing to not only fund the lab for me but was willing to give me a reasonable raise in salary, so I moved, the whole family moved across, that's Kathy and me, just us. Moved across the country to Stanford, and I was able to set up a lab because there was some space that nobody wanted in the basement of the Haren Laboratories. The oldest biology building in Stanford. And that was perfect because the work that I do is so sensitive to noise and vibration that you want to be well away from roads, you want to be in the basement of the building so the vibrations of the floor were not a problem. And this building was perfect for that. It was the old kind of building. The kind that falls down as soon as there's an earthquake. New buildings are built to bend like a bamboo in the wind, so that when the earthquake comes, the building gives. That's precisely what you don't want for a nanoscale measurement because the floor's always moving at some level, whether you want it to or not. What you want is the old kind of steel or brick and heavy stone building, which is set to collapse upon you the minute the big one hits. And that has the advantage that until the big one hits, it's relatively free of noise and vibration. And this building was, had a berm around it on two sides that was well away from roads and the space that I- and also had what was called a slab cut perform, which is to say that someone was trying to do low-vibration research in the past, and they cut this concrete slab of the floor away from the superstructure of the building. So, if the building moved even a little bit, the concrete floor would essentially float. This was done, I was told, for of all things because somebody was working on ants in the lab previously. And apparently ants are very sensitive to ground vibrations as well. So bottom line, they moved me into some fabulous space. They built a lab to my specifications. They built it on time and on budget. Which is a good thing. And it took only a few months after we got there, and everything was working beautifully. Of course, you need things to be temperature-regulated too. If there's even a fraction of a degree temperature differential across the room, metals of which the microscope is made will expand and contract and they'll move at angstroms a second, so if you're trying to measure angstroms, you're sort of out of luck if there's a temperature gradient. So, you need to build a temperature-stabilized, vibration-isolated, soundproofed cleanroom to do the kinds of work that we do. So, it has a cleanroom entrance with a gowning room and sticky pads on the floor and has acoustic isolation inside. It meets the so-called OSHA NC-30 noise standard, which is not quite you can hear a pin drop, but more like a quiet bedroom at night kind of noise, without the snoring. And the lab was duly built, and it was in that lab that we were ultimately able to measure these 3.4 angstrom steps, moving on DNA.
So, you're a happy boy at this point?
I was a happy boy at this point. Everything was happy until about two, three years ago, when everything went south. So, I had some great students, by the way. One of them, Josh Shaevitz, actually not only finished in my lab, but today is a professor in that same Princeton physics department that wouldn't accept anybody when I was there. So, the irony now is that one of their leading biophysics is my former grad student. So, you know, they say, living well is the best revenge. This, I think in academia, this is the best revenge. So, everything was fine until about two or three years ago, Stanford decided to embark on a pattern of construction all over campus. So, they have lots and lots of money at Stanford, and they decided that the best thing they could do is build new buildings. And the phrase is that Stanford has an edifice complex.
One of the problems is that next to the building where I worked was the old chemistry department of Stanford. Now, it was one of the original Stanford buildings built one hundred years ago. It had been damaged in the earthquake, which was, you know, now twenty years ago or whatever. And had been closed up and had a fence around it. The reason is that they couldn't open it up until they brought it up to code. They couldn't bring it up to code because it was the chemistry building, and modern chemistry buildings require fume hoods, they require epoxy floors, they require certain special types of lighting and electricity, so they don't blow up. All sorts of precautions. And the old chemistry buildings were nothing like that at all. So, it sat there unused for many, many years until Stanford decided to turn it into a teaching and learning center. That involved taking the building, gutting the entire insides, turning it into a shell, and then building a 500-seat auditorium underneath it. So, you can imagine the amount of earth moving involved to do that. And this is all taking place within fifty feet of my building. So, the noise and vibration were absolutely hideous. They were so bad that you could put a glass of water down on our conference table and you could see ripples in the water. You didn't need a special instrument to detect nanometers to do this. The noise levels were so high, there's no way we could make any nanoscale measurements at all. But it was going to be okay, and the reason it was going to be okay is, they realized this before they started the construction. We had an agreement with them that Stanford would pay some extra money, and they would start the construction at three or four in the morning and they would continue until noon, and then they would stop construction, and so we would have the afternoons free to take our data, and the mornings would be noise from construction. And that was fine by me, and we shook hands on this. But the construction started, and almost from day one it was clear that they weren't going to abide by any of this. And at first it was, well, they stopped at noon, but they needed to put all their bulldozers back in place, and that took them another hour. And there were a few additional things they had to do, that took them another hour. Before we knew it, they were working until three, four, five in the afternoon, and there wasn't a damn thing I could do about it. I lodged complaints with the deans, so forth and so on. It was all to naught. I started writing letters. It turns out that the only time we could collect data were either nights or weekends. We eventually lost the weekends as well, because the construction was behind schedule, and they started working weekends to try to make up the schedule. So that left only nights. You could only work after dinner until dawn. And my students didn't want to do that. I didn't want to do that. I went to the deans and said, "Look, we had an agreement." The deans decided that they were hemorrhaging money by paying for construction to start early, that construction was a higher priority for them than my work, and they thought that what they'd do instead is they'd give me some extra money. And if they gave me the extra money, I could give my students a raise. And if I gave them a raise, maybe they'd work nights.
I thought this was laughable. You laughed; I didn't even have to tell you the next sentence. You can imagine the next sentence. This did not work. Some of my students would work nights. I mean, all graduate students have the experience of working the occasional all-nighter. This is perfectly normal.
But not as mercenaries.
Right. But not as mercenaries, and not as the only mode of working, right? These people have lives. Some of them have boyfriends and girlfriends and they want to go to the movies, and they want to have fun and they want to- some of them live in San Francisco and need to commute. For a variety of reasons, grad students will not work the night shift. Only. And they didn't sign on for that in the first place. And so, what happened is, my lab started hemorrhaging people. And the postdocs would leave, and the grad students would graduate out. No student, for a period of two years, not a single student volunteered to rotate in my lab because the word was out, if you want to work for Steve Block, you've got to work the midnight shift.
And relocating was just not an option?
No, because Stanford was on such a plan of construction that there were at one point no less than fourteen different construction sites all around campus simultaneously. So if you say, "Look, I've got to be near a certain amount of bedrock, I've got to be a certain distance from a road, and I've got to be a certain distance from a construction site," there was literally no place on campus that they could put me. The medical school, for example, is built on old landfill from the San Francisquito Creek, which was- and so that, most of that area is not amenable to this kind of work. The old physics department, old Varian, had some spaces in it, and they did renovate a space for Hari Manoharan, who worked on scaling tunneling microscope. But he occupied that space and so there was no space for me over there. And besides, physics was not my department, it was applied physics. Applied physics had some space over in the End Station III at Hepl, but the university had taken that over for some administrative offices, and that was not a space. To make a very long story short, there was no place to move me, and even if they had moved me, it would have taken them two years to build a special soundproof, vibration-isolated, electrically isolated cleanroom. And they didn't have the budget or the time to do this, and regardless, I'd be out of work for two years.
And were you unique in terms of faculty whose academic life was essentially ruined as a result of this? Was there a groundswell of support because it was not just you?
No. In fact, it was disappointing, because the one person who might have supported me was W.E. Werner, also a Nobel laureate in chemistry, but was also trying to do some single-molecule biology. But he was doing what's called single-molecule fluorescence. And being able to take a florbaflor, which blooms out to the diffraction of the microscope and therefore looks, perhaps, 200 nanometers in diameter, and being able to do what's called super-resolution microscopy, which pushes that down to maybe, you know, five nanometers at best, usually fifteen nanometers is a typical number. Is still an order of magnitude, or perhaps two orders of magnitude, bigger than the distances we were looking for. And so, a lot of these vibrations in practice did turn out not to bother him at all. And so, he wasn't much of a voice of support, because it wasn't his ox that was being gored.
So, it was just yours, that's it.
It was just mine. And so now we fast-forward two years later, and comes the final blow, which is they've decided to build a new biology building, and they decided the old building that I was in, Haren, would be torn down. Why would it be torn down? Stanford has something called the GUP. The General Use Plan. Stanford has an agreement with the surrounding county, that although it has a great deal of land, it will only build a certain number of square feet per year on its campus. In return for permission to keep going to get various special favors from the county, like building a road that would handle the traffic going into Stanford. So, Stanford over the years, for example, has made footpaths available to the community or set aside spaces as open space, and the county has been very reluctant to allow Stanford to do massive building programs on campus. For a variety of reasons, some of which are perfectly reasonable, because they don't want, you know, unbounded expansion taking place within their community. Stanford's already the largest employer in the area, and it contributes hugely to the traffic, and to pollution, and to other things. So there's this thing called GUP, which comes up every ten or twenty years, and it is a deeply political and widely fought, and people go to city council and stand up and yell and scream, and the university's lawyers get up and they carefully negotiate how many square feet Stanford may build, say, in the next ten, fifteen years. And part of that GUP is that if they want to build new spaces, often they have to tear down other things. In other words, they're allowed a certain number of square feet, and the only way to build a new building, in some cases, is to tear down an old one. And so, it was deemed that the building I was in would be torn down in favor of new construction for other purposes under the GUP. So, they decided to build a new biology building, the Bass Building, and I was told that, you know, I would have to pack up all my stuff and leave and move to another building. And there are two problems with that. One is they would have to build the same specialized laboratory. I'm talking about inside the new building. And the other problem is that the kind of work I do is on these enormous air tables that you often see in optical physics labs. They're a foot thick, you know, twenty feet long, six feet across, weigh a ton, and have on them various types of optics and microscopes and lasers and they're very heavy. You can't get them out of the rooms there in the basement without removing all the parts that are on the top of the air table. That means, basically means dismantling apparatus, which in many cases takes a year or two of graduate work just to build, and another year or two of graduate work to calibrate and get working. So, I have apparatus, custom apparatus in four different rooms, which was built. It took a better part of the decade to make it all. And it would have to be torn down basically to bedrock in order to free up the air tables, so they could be turned sideways and maneuvered through the doors through some elevators and into the new building. In one case, they actually had to demolish part of a wall to get it out. So that meant that whoever stayed in my lab would not only have to take it apart but would have to put it all together again. Nobody wanted to have that kind of interruption in their graduate career. No one wanted to go through this at all in the first place. And so, by the time this was announced, everybody in my lab left.
Steven, I'm wondering if at this point you were rethinking maybe following in your father's footsteps and doing theoretical physics (laughter).
Yeah. Well, that's a bit of irony. I didn't mention it early, I probably should have. And maybe you can shove this into the early part of the transcript. But my father retired from Northwestern as an experimental physicist in the seventies, and moved everyone to Aspen, where he became a theorist. And to the best of my knowledge, there are not many experimentalists who went on to do theory. Of course, there were some famous people who did both. Enrico Fermi, of course, is probably the last greatest physicist who was world class in both areas. So, but my father basically turned, became a theorist, and for the next twenty-two years in Aspen, right up until his death at age ninety-two, was doing theory. And in fact, in his last year of life, he published more papers than I did.
(Laughter) Wow. Physicists never retire, by the way. I've learned that.
I guess. Mathematicians, of course, famously are not known for producing anything after age thirty-five, which is why the field's middle has an age limit on it. And there are few notable examples of mathematicians who contributed, but not many. Physics is kind of an open book. Hans Bethe was active until the end. My father's first paper was published, I think, in 1949 or thereabouts? And his last paper in 2000 and something. And at one point, the editor of Phys Rev Letters wrote to him and said to the best of his knowledge, he had the longest-spanning publishing career in Phys Rev of any author. I don't know if that's true or not. The editor seemed to be of that impression. Anyway, that should probably go earlier in the transcript. Back to our story. They marched me into the new building last year, except there was a problem. The new building is supposed to be a so-called "green" building. That is to say, it's supposed to sip energy and not use it too much. So, a great number, and this is both a requirement of the GUP and also because of Stanford's desire to use less in the way of fossil fuels, but for a variety of reasons, they failed to design the HVAC in my lab properly. So the way HVAC normally works is you bring in chilled water, you cool the air below the temperature that you really would like to have it at, and then you rewarm it with a heater up to exactly the temperature you like. And then you can apply PID control to the heating elements and you can get very accurate temperature control. And so, this is a desirable way to keep the temperature right, because the temperature needs to be clamped to within about +/- half a degree Celsius, a quarter a degree Celsius, actually, in the rooms where I do work. Because if it's not clamped to that level, you get drift due to thermal motions. So, they screwed up big time on that, and when they built the new building, they mixed some of my incoming air with air meant for the building. Instead of giving it a separate feed. And made a number of other errors. But the net result is they to this day, now a year and some months later, are still not able to regulate the temperature of my new rooms in the new lab. So I'm in the horrible situation where I have no people in my lab, apparatus is all in pieces, and even if it could be put back together again, there's no opportunity for doing any science because they can't regulate the temperature. Now they should have-
So maybe coronavirus has not been so bad for you?
Well, the irony is that I was experienced lockdown and pandemic before any of my colleagues.
So, the only thing I've transitioned into is they don't let me in my offices. To this moment, we are still locked out of our faculty offices and buildings at Stanford. Those, they have key card access and they disabled all our key cards. So, they're slowly starting a return to work this week, in fact, but I haven't been able to visit my office in nearly two months. Meanwhile my computer server went down and won't respond to foreign commands, so I have to reboot something when I get back. But Stanford has unfortunately really put a kibosh on my further career. I probably have published my last paper on optical trapping. And it pains me enormously. So, I've been going through my own share of difficult times. Everybody else is experiencing a momentary stoppage of their work. And I've been dealt a more or less permanent stoppage.
Whew. That's very difficult to hear. What, have you thought about leaving Stanford? I mean, is it easier to reboot somewhere else?
Well yeah, I could. Yeah, if I were twenty years younger, I would have told them what they could do with their construction and left the university. There are several problems associated with that. One is that both my wife and I are approaching retirement age. I'm sixty-seven now. My wife is scheduled- she runs the library in Belmont, California. She's the manager. She's approaching time of retirement next year. Were I to move to another university, I would have to build up a group, I would have to be there long enough to see a few graduate students through, so we're looking at least six to ten years. And it would take them a year and a half, two years to build kind of lab with the type of temperature regulation required for me to do work. And of course, once I moved there, it would take a year or two to develop the apparatus and bring it back. I mean, this is one of a kind, specialized apparatus that's not- you don't just pick it up and move it. In fact, Stanford wasn't able to pick it up and move it one hundred yards, let alone across the country. So, if I were twenty years younger, there's no question that I would have been very unhappy with what Stanford has done to me and I would have left. As it is, I have indicated to Stanford that I will spend a year on sabbatical this coming year, but the pandemic has really dealt me a number on that. So, all the planned travel is now up in the air, all the lab visits are now up in the air. And then I'll come back for a year of teaching and then I'll have to go emeritus. But it's been a very rough year for me this past year.
And emeritus for you, I mean, what does that even look like?
I don't know. Well, of course, people keep talking about the "new normal" now after the pandemic. And I have no idea what this new normal will represent.
But there's no remote work for you if the heart and soul of your work is the lab.
That's right, that's right. I mean, this is the curse of being an experimental physicist, is you live and die by the apparatus you have. And you also live and die by the people that you can have in your group and collaborate with. The work I do is not the sort of thing that a solo person pursues, you know, in a study. A theorist could perhaps make do with a computer and a pad of paper, or maybe even less, but an experimentalist really relies on apparatus and on people and on collaborations. And basically, all of that has been blown apart by these things. So. I've been an unhappy camper for a little while now. And the best I can hope for is that, you know, I can contribute in other ways to science. So, my wife keeps trying to get me to write a book, for example. I'm not sure I want to do that. Although I did win an award for writing once (laughter). It's been a while.
This is so clearly a cautionary tale of, you know, how aggressive a university can be, and in doing so, losing sight of what they're really there to promote in the first place.
Absolutely. I think I was sacrificed on the altar of progress here. I think Stanford in its headlong pursuit of new initiatives has failed to cater to its existing faculty. The latest controversy at Stanford is they want to create an entirely new school. The School of Sustainability. The problem being that no one can agree on what sustainability really means. And there was a lot of opposition amongst the faculty, because although this is trendy and certainly can, the development office will have a field day raising money for this, it cuts across the fundamental disciplines in ways that only drive people apart rather than bring them together. So, they're going to be, you know, cherry-picking faculty from various different departments and moving them over into the new school, and biology department in particular, you know, has some people who do ecology and evolution and it's not clear where those people are going to go in this new world of sustainability. And they, you know, they create an institute which is going to receive a lot of attention and a lot of funding, but this is to the detriment, I think, of the fundamental disciplines. And remember, we talked a lot about the fact that I view biophysics as a way of understanding at the fundamental level how biology works. And the physics, I think, is the ultimate in fundamental sciences. And these are precisely the enterprises that I think get hurt when the resources are shifted wholesale over into enterprises that, while being politically trendy, ultimately don't qualify in my view as serious disciplines. You know, if you really want to do science, if you really want to understand how the world works, that's one thing. If you're interested in social science, if you're interested in, you know, helping mankind, sustainability is probably as good an area as any. But, you know, you asked before about whether I was interested in medicine, and I'm not opposed to medicine. I think medicine is wonderful. But we need better medicine, better doctors, better health. But that's not what I want to pursue. The world needs sustainability, or better yet, we need to worry about things like climate change and adaptability, and taking care of the Earth, and keeping our resources in check. We need all of that but that is not the discipline that I signed up for as a scientist.
You described yourself before as somebody closer on the atheist side of the scale. To the extent that you believe, though, that the universe might have messages for you, perhaps one of the messages is, you know, you have ways to contribute and sixty-seven in an academic life is, you know, you're a young man, right? You have ways to contribute and maybe there's a reason that the universe isn't allowing you to continue what you thought you were going to continue to do?
Well, yeah (laughter). That is a viewpoint.
I'm encouraged by your saying that sixty-seven is not that old for a scientist. Of course, you know, the retirement age is getting higher and higher. But one can make the case that-
What I mean to say by sixty-seven is, you're a young sixty-seven, and I mean that because you have so much energy and frustration in the way that you're expressing all of the things you had planned to do.
So, the momentum of your sixty-seven-ness is young. That's what I mean. It's not an objective number.
Yeah, it's true. One can make the case, I suppose, that the more people my age get out of the system, the more available it is to a younger generation. And a lot of that generation, because of limited resources, is being cut off. Millennials in particular are not enjoying the lifestyle that my generation had, or even my parents' generation had. Arguably, my parents' generation did better in terms of cost of living than I did. And the next generation is doing remarkably worse. So maybe we need to put a place, or find a place, for the next generation that's coming up. And so maybe my forced retirement is not such a bad thing after all. It certainly feels like a bad thing to me. But whether that's a bad thing for society is a different question. You know, years ago by Supreme Court ruling, the United States stopped mandatory retirement in a lot of areas. It still takes place in Europe, for example. And one of the consequences of that, maybe an unintended consequence, is a lot of European scientists facing retirement in Europe, came to the United States and finished off their careers here. So, we got kind of a brain drain out of that.
So, Steve, let me ask you a question that could prove to be quite productive in the vein of if you were twenty years younger, right? So, you appreciate the context here, we'll get this interview published at the Niels Bohr Library. We will tweet it out to our not-insignificant number followers. It will get picked up by people that see your name and are aware of what you do. And there will be somebody who is going to pay very close attention to the question I'm about to ask you now, is: if you feel like your own research and your own life can't continue, that's certainly a very separate statement from, somebody sort of picking up where you left off who's thirty or forty years old, who's at a different university, who's building the lab, who believes in what you do and sees the future in it, right? What's your message for that person? Or if you could become that person, how would you continue looking to the next decade?
Well, if I could say it one sentence, it would be, "Get it in writing." The one thing that's happened throughout my academic career is that various agreements with deans and administrators and department chairs have all been oral agreements. They have not stood the test of time. It is not a coincidence that deans and administrators would prefer to call you on the telephone than to send you an email. Because so much of the business they conduct is ephemeral and it works to their advantage. The universities, in recruiting faculty will often make certain promises, but I have had a career which is filled with various types of broken promises along the way. That's not to say I'm not grateful for the work I've been able to do, the resources I've been able to get, the students I've been able to get. All that's been wonderful. But insofar as I've had problems, they've almost all been associated with various remonstrations that were made that turned out in the fullness of time not to be worth anything. And Stanford, you know, built me this wonderful lab. But they also took away that wonderful lab. Stanford made me promises about being able to have certain awards and nominations. Those didn't happen. So, a lot of things turn out not to play out in the fullness of time, and I think it's partly because of the way universities do business. And their goals and aspirations are not the same as ours. I mean, one example of that is that we're required by law in California to undergo training in sexual harassment every two years through the university. I must have a dozen such certificates now on my wall for having gone through ten or twelve sessions of sexual harassment training every two years. Originally, that training was more like a kind of sensitivity training about how important it is, and I agree with this, to treat people with courtesy and with deference and with fairness. More recently, sexual harassment training has been, in my view, more about protecting the university against lawsuits being brought by Title IX for various insults performed by its faculty or its administration that violate the law. So there, things are increasingly being written by lawyers and they're being done to protect the university, rather than, what I would call, the right reasons, which the right reasons being that, you know, sexual harassment is just wrong, and that we should treat people with respect and with dignity. And respecting of who they are. We're seeing that play out now with the Black Lives Matter movement, we're seeing this play out with the immigration concerns, all over the place. I think the problem with the universities increasingly is that they are more concerned about their image and about their lawyers than they are concerned about what, you know, what is right and wrong. Now, this may be a jaded perspective based on my own personal experience, but you've asked me what advice I would give people, and when I said "get it in writing," what I meant by that is that if they make promises to you of various different types, you need a record of those promises, because the sources are not trustworthy, and even if the sources had the best of intentions, the fact of the matter is that in academia, there's a certain amount of personnel transfer, turnover, excuse me. Certain amount of personnel turnover, and they lose corporate memory. They lose memory of all the things that they were going to do for you, and all the help they were going to provide for you, and so forth and so on. There was another episode at Stanford I didn't even go into, which is that I went to Stanford in part because I was joining something called Bio-X, and they were building a new building, which you can have a special lab in it for me. The lab that I told you about, by the way, is only a temporary lab that was only supposed to last for six months after I got to Stanford. It's the one I wound up working in for twenty years. Why? Because I was supposed to move to this new building with this fabulous new lab. Well, when they built it, that lab too didn't fulfill the specifications that were down there. And I fortunately had some of that in writing, and I told Stanford this is not going to work, and they allowed me to stay in the temporary space. So, it's ironic that this- but this is the second time that Stanford's tried to move me out into quarters that would not have allowed us to do the kind of work we did. If I had moved into the new building of Bio-X at the time, I would never have gotten my work done.
Now, the advice you gave was administrative advice. And I was also asking about the scientific advice, the way that you would continue that lab if you were that thirty-year-old in a new place with a brand-new lab that was essentially picking up where you left off.
What would you hope to accomplish in the next decade?
Thanks for clarifying that. So, in terms of my own research, there are a number of outstanding questions that I'd love to go after, right? So that, in biology one speaks about this so-called central "dogma," this is the flow of information from DNA to RNA to protein that makes possible all of life. And the biggest question in biology, arguably, is the question of gene control. The difference between the tip of my nose and my liver and my bones is not that they have different DNA, it's all the same, but they have very different patterns of expression of that DNA, which lead to, you know, different parts of an organism. They’d lead to very different fates and very different trajectories. So, if you want to understand life, you really need to understand gene control. And there are a number of enzymes that are involved in that. We talked about RNA preliminaries, but there's also DNA preliminaries and various transcription factors and isomerases and gyrases and so on. All of these are grist for the mill. All of these are enzymes whose mechanisms are only poorly understood, and we'd love to understand how it is that they actually work. We'd love to understand more deeply the mechanisms of gene control, and there aren't just one or two, but a great many, it turns out. If you can think about a way of controlling genes, chances are, nature has figured out a way to do that and has implemented it, it turns out. This is worth an entire lecture, but I won't do it. So, if I had been able to continue in science, I would have loved to have gone after some of these other enzymes and understand gene control a little better. In the last three years, I've been working on something called ribose switches. It's a term that was coined by Ron Breaker at Yale. A ribose switch turns out to be a very ancient form of gene control. it predates the proteins sitting as repressors on DNA and repressing genes. It doesn't involve proteins at all. It probably predates the existence of proteins. A ribose switch is a piece of RNA which gets transcribed but not translated. It's not made of proteins. It sits upstream of the genes that are actually going to make proteins, and it folds up into a particular shape. And that shape acts like a switch. That shape can actually bind and sense molecules in its environment. It can sense specific ligands. And depending on whether it senses or doesn't sense the ligand can turn the gene downstream of it on and off. So, it's a ribonucleic acid switch, or a ribose switch. So, our lab has been able to study how these things fold and unfold with optical traps. We were able to do all of that, and there's a whole world of ribose switches and we were only just getting started on trying to dissect their mechanisms of gene regulation. We had one or two papers on ribose switches, which have been very interesting to me. So, had I an opportunity to continue, I would have certainly worked with ribose switches. Had I an opportunity to continue, I would have certainly worked on other proteins of the central dogma, that help to carry out gene expression, and all with the theme of trying to understand how proteins move, how proteins control other proteins, and how genes are regulated. It's all part of the same kind of raw puzzle. But that's my passion and that's the passion that unfortunately is being brought to a premature halt by forces beyond my control.
Well, Steven, let me ask you, you know, as we get towards the end of our interview, some happier questions that ask you to sort of broadly, you know, take a retrospective view of your career. And the first one is, you know, in terms of your contributions, the way that you look at your contributions. Is there a single project or research endeavor that stands out or do you tend to look at the whole corpus of your research as sort of contributing to a particular area of knowledge, and that area of knowledge is the contribution as your see it? I'm just curious, you know, intellectually, how you understand your contributions.
That's a very interesting question. I push back a little bit in the sense that it's a false dichotomy. That the two are not mutually exclusive. And while it is true that there have been highlights, if you will, of my career in which we were really trying to do something and finally got it done. Some of the highlights I've talked about already. Seeing the first steps of the bacterial motor and velocity as it- which told us so much about how the motor must work. Seeing the first steps of kinesin, which also told us about how that motor worked. Seeing the steps of RNA preliminaries, which did that. And then finally in more recent work, watching the folding of nucleic acids, which can fold up into these very interesting shapes that are capable of ketolysis and capable of gene regulation. Watching those little folding steps and each piece of RNA snaps into place and makes it a little shorter, and measure what we called the folding energy landscape. All of those things had been breakthroughs in a scientific sense, because they were goals of the research before, we could do the research. And they became accomplishments afterwards, and in all cases, they provided new insights. And in all cases, they provided real challenges for follow-up experiments that would, you know, if you could do that, then you should be able to do this and this and this. So absolutely, it is true that I could point to four or five or six independent highlights of my career, all of which got me terribly excited, renewed my spirit for science, kept me going for the next decade, and in the retelling, I always have a warm spot in my heart. That's true. But it's also true that a research career has a kind of trajectory to it, in the sense that you alluded to. And that I do consider myself, first and foremost, a biophysicist. And by that, I mean I want to use not just the techniques but the mindset of a physicist to address biological questions of interest. Maybe the difference between a biologist and a biophysicist is not so much the exact questions they ask, but the way in which they go about seeking their answers. I use technology that most biologists wouldn't easily manage or appreciate. I mean, in my work, you not only have to know about microscopes, but you also have to know about optics and lasers and Fourier transforms and, you know, decimal points of measurement. Phase lock loops and things that, you know, most biologists don't get to hear about. But in my work, we also day-to-day need to run gels, clone genes, isolate proteins, develop single molecule assays. And that's work that a real biologist needs to know. The students who come out of my lab, I think one of the reasons they've been so successful in academia, is they come out with massive skills. They can not only handle a number of things that only physicists can do, they can also handle a lot of things that only biologists can do. So, in terms of stepping back from it and looking at the broader trajectory and asking, "Has my career had that kind of an impact?" I would say yeah, insofar as I'm proud of something, it's that I'm part of a series of generations which since World War II have really shown that you can make serious inroads into biology from this physics perspective. So, the first generation of people were people like Max Delbrück, who came out of physics with no background whatsoever in biology, and then made strong contributions ultimately, in Max's case, the Nobel prize, in biology. Wally Gilbert is another example. PhD in physics, a theorist who helped develop DNA sequencing. Francis Crick. There's a generation of people in the fifties going into the sixties, Seymour Benzer, Sydney Brenner, with strong physics backgrounds who, or biochemistry backgrounds, who made contributions to fundamental biology. Then the next generation after that, people like Howard Berg also had a physics background who did this. Then came, I think, my generation, and now we have a third or fourth generation of people including some of Howard Berg's other graduate students. Markus Meister, who's a neuroscientist at Caltech and Karel Svoboda, who's at Janelia Pharm, and Mark Schnitzer, who's a Howard Hughes investigator at Stanford. Some of them work in neuroscience, some of them work in biophysics. But they're all using physical methods and a physicist's perspective on measurement and observation and bringing that to bear on biological questions. And so, I think I'm part of a generation that's kind of carrying a torch in a particular direction, and I see that as having a rosy future. This stuff is, this is not going to be, you know, my own research may be on hold for the moment, but this is, the field is not going anywhere right now. It's growing. It's been my privilege to run for the last twenty years this single molecule biophysics conference at the Aspen Center for Physics. We do this every other winter. And it's been sold out every single winter. it's the largest conference they have. It's arguably the most successful insofar as we've raised the most money, we have the greatest attendance, the field is going gangbusters. And so, I've been able to see this field of so-called single molecule biophysics grow from nothing. It didn't exist in the sixties. In the seventies, Nerid Sackman showed you could look at single channels, but then nothing happened until about the nineties. And since the nineties, we now have the growth of a large number of ways of looking at molecules at the individual level. People are now talking about doing single cell PCR and looking at the genetic complement of a single cell. They talk about single molecule folding and unfolding experiments. Trying to understand how proteins and nucleic acids assume their shapes and undergo reactions. And so, it's very, very lively field today. And it grew from nothing. So, the answer to the second part of your question is do I see a trajectory, do I see my career as amounting to some contribution to science. I would say with some immodesty, I'm afraid, that I'm very proud to have been one of the founders of the field of single molecule biophysics. And I'm delighted to see what a strong field it is today. And how it's grown over the past twenty, thirty years to become a central branch of biophysics. I remember when there was perhaps one or two posters at the Biophysical Society meeting out of order of 5000 on the field of single molecule biophysics, and now if you go to one of their meetings, the mean free path between such posters is like twenty feet in a giant convention room floor. And so, there are literally hundreds of posters on single molecule biophysics. So that's been a seat change, and for me it's been a source of immense pride and gratitude.
It's been, it's so obvious in listening to the way that you talked about your two main mentors that, I mean, I don't know, maybe the best word is you were blessed with having two mentors, not just one. I mean, people would kill to have just one of the kinds of relationships that you had. And you had two. So I wonder if you can talk, not just about learning the day-to-day, in terms of lab work, but how you learned from both of them in terms of how to be a scientist, and in turn, how you have transmitted that legacy to your own students. And again, you can be modest in that regard, in terms of it's all about their success and their hard work, but clearly there is that connection with you in the middle, in terms of what you have learned and what you have transmitted.
So, you know, mentorship is an interesting thing. It's something of a moving toy shop in my own experience. I've been mentored in many different ways. I mean, growing up as the son of a physicist, I had a kind of a mentor in the field. And I took away, in some ways, a negative lesson from that. There were things that I knew I just really didn't want to do. On the other hand, it was part of my upbringing and it was instilled in me, and I had this, you know, amazing experience from an early age being able to do interact with some of the great scientists of our age. But just as a little kid. Then came Max Delbrück, and I think from Max I learned, more than anything else, about how one act of incredible generosity can transform a person's life. Max went out of his way to bring me to Caltech for a year. He literally took up a lectureship and turned all of the money into the Steve Block fund. And made it possible for me to come out to Caltech for an entire year. And personally shepherded me into the field of biophysics. A debt of gratitude that I will never be able to repay. And then not only that, he arranged, he literally arranged for my doctoral advisor. He picked Howard Berg and said, "This is the person you want to work for." And so, in some ways, he planned my career for me. And I was young and naive and I was, for whatever reason, I didn't rebel against that. So, I went with it. But I had a lot to learn, and I was, you know, like a lot of scientists who I know, particularly at universities like Stanford and Princeton and Harvard, all the three, and Caltech, all the places I've been, these are amazing people. They are not just smart, but they have all kinds of other talents. Sometimes talents that they've never tapped or never deeply explored, but talented, nonetheless. Some of them are great mathematicians. Some of them great chess players. Some of them are great musicians. Some are great mountain climbers. But amazing people, and I think what I learned more than anything else from my experience with Howard, is that you can culture science in a person, but you can do it in a way that doesn't necessarily cut them off from all these other avenues. And that you need to celebrate all aspects of people and you need to give them maybe just enough rope, so they hang themselves. And hope that they don't. I've had some students that have just not done that well, not thrived, but the students who have thrived have really thrived because, I think, I don't micromanage them. I don't look to tightly over their shoulders. I don't come up to them every day and said, "What have you done for me lately?" I imagine that they're going to be doing great things. We meet, you know, once a week or thereabouts in group meetings and so forth and we talk about how things are going. But the students who've done best with me in retrospect have been the ones who had something deep inside them that motivated them, that kept them going, and that something played against all their other interests as well. You know, these were not one-dimensional people who pursued science and nothing else. They were not obsessive. They were polymaths in many cases. And if I look at the great scientists that I admire, the Howard Bergs of this world, Max Delbrücks, the Ed Purcells, these are also polymaths. So insofar as, there's a lesson here, I think it's that science isn't just about something, science is about everything.
And so how do you mentor everything in a person? And of course, the simple answer to that is you can't. It's just not possible. There's this quote in the beginning of the Feynman Lectures in Physics, which you may know, from Gibbons, which is, "Education is seldom of much efficacy except in those happy dispositions where it is practically superfluous."
So, you know, my father gave me Feynman Lectures in Physics when I was still in high school. And I really couldn't quite appreciate it then, but I start to read it more and more later. And of course, as you know, it's a book best read when you already know the physics and not trying to learn from that. It's maybe hopeless. Although you could learn about the style of Feynman, you may never learn some physics. I think, you know, I have been very lucky, because I've been blessed with some people who were just extraordinary and self-motivated. And in some ways, I felt that all I really did was wind them up and let them go. But insofar as I would take credit for anything, it's that I gave them a place where they could be wound up and let go. I gave them a place where getting wound up was an okay thing to do. Being let go was an okay thing to do. And one of the things that I learned, for example, is to try to build up their communication skills. And I spent a lot of time, particularly, and this is something that I think a lot of physicists neglect altogether, you get my students to both speak and write well. And this has had real, serious impact, I think, on their careers. And I learned it from Max Delbrück. Max would have weekly group meetings in his group, and he would make everybody get up and give a talk. In turn, maybe they wouldn't all get to be one week, but everybody in the group gave a talk. This includes the janitor who helped clear out the things, and there was a woman who ran our autoclave. She would have to get up and talk about what's up with the autoclave. And I would have to get up. I was just a summer intern, or basically a student helper. And Max would stop you after a few sentences and say, "That's not the way to say it. This is how to say it." He would stop us in our tracks. Of course, Max didn't win a lot of approval for some people because he was famous at getting up in lectures. He didn't suffer fools. And so he was famous at Caltech, he would sit in a lecture, somebody would even be giving, for example, a tenure talk, and Max would always sit in the first two rows, and halfway through the lecture, if he didn't believe what he was hearing, he would get up and say, "I don't believe a word of it." And he would turn around and leave (laughter). So, this did not endear him to some people. But what Max did to, to his credit, was that he really taught you to think about how you're saying something. And he taught you to think about how you would communicate to somebody who's not necessarily an expert in your area, and how would you get them to believe that what you're saying is even the slightest bit important or interesting. How to make something interesting to somebody else. And I think, insofar as I've been able to get any awards for my teaching, it's because Max taught me. And Howard Berg later on also, superb writer, I would send him a page of what I thought was careful prose. It would come back with entire paragraphs exed out. He'd say, "You don't need to say this, you don't need to say that." Brevity and pith were the two words that Howard Berg would concentrate on, and he would have a way of saying something which by the time he wrote it, it was remarkably simple. It didn't use a lot of complicated vocabulary that, you know, you don't ever elucidate something, you just show it. You know? You don't- and so, he got rid of a lot of the silly prose that scientists tend to write with. He would write something very simply and very straightforwardly and I learned a lot from that. So my writing improved enormously with Howard, my speaking improved enormously with Max, and one of the things that we always did in our group is we'd have everybody get up and give practice talks and practice talks and practice talks and we would be relentless in criticizing them. They would get in three sentences, we'd stop them right there and say, you know, "That slide, the wrong font. That slide, the graph is invisible. What you said about it, that's not what you say. This is how you say it."
So, this was, and this worked out really well. I mean the most famous story surrounding that is that I had then a postdoc who's now a professor at University of Washington in Seattle. The same university that I went to all those many years ago. And he was finishing up some work, beautiful work on kinesin. I think I alluded earlier to the fact that under some conditions, kinesin will actually limp, take more time for the left step than the right step. And this of course tells you that it alternates its feet and tells you a bunch of other stuff. He had been at the University of Washington before this, and he was an avid sailor, he loved to sail, and his dream job would be a professorship at the University of Washington. He wanted no place other than that. He'd been an undergraduate there and he really wanted to go there for the rest of his life. And they had a job search at the University of Washington in his area, but his paper came out a bit late, and the job search had already been closed. And so I got on the phone and I called the people who were responsible for the search, and I said, "Look, I know you may have already made your selection, but if you haven't told them yes or no yet, you should definitely at least hear this guy out. Hear him out. You might change your minds, and if you don't, it's very little ventured." So, I convinced them to hear him, but the problem was that he had forty-eight hours to get up to Seattle and give a talk on something that he'd never prepared a talk for before. So, in the first twenty-four hours, we had him prepare a talk, and the next twenty-four hours was nonstop grilling him about how to give a talk, and we made him change this and change that and change this and change that. And really put him through the gauntlet on his talk. He went up there and he knocked it out of the park. And although they were, you know, this close to calling somebody, their first selection up and giving them the job, they instead gave it to Chip, and today he's happy as a clown up at the University of Washington. So, and he would probably also credit, if you asked him, the practice talks that he gave in our lab for a large part of how he was able to convince the faculty to hire him. And as I've talked to graduate students over the years, one of the things that they often come back with was, "Oh I remember the practice talks in the Block lab. I remember how you raked us over the coals on how to either write something or how to say something. Or I remember writing that manuscript, how painful it was because you kept crossing off my paragraphs and putting in these other things. You would rewrite everything I said. You would undo everything I tried to communicate. But boy did I learn and today I think back to that every time something goes well" (laughter).
Well Steven, for the last of my retrospective questions, and then I'll have one final question that's sort of a forward-looking question. And I've been excited to ask this for hours now, because both your personal family background and your educational trajectory and your entire research career just lends itself so beautifully to this question, which is, whether it was something that you learned in high school physics, or at Oxford, or maybe something that you just felt like you needed to teach yourself, what are some of the fundamental concepts in physics, or ways of thinking like a physicist, that have informed your work in the biological world? Not just on a, like a grand scale, but the concepts or the laws or the mods of thinking that you have an affinity for, that stay with you day to day, that really inform how you put together a project, how you advise a given student. What are those concepts in physics that have always been with you in the biological realm?
Sure, well. You know, for most of biophysics, with the rare exceptions, things like relativity, gravity, and even quantum mechanics are scarcely applicable. There's a small application of quantum mechanics to proteins that are a sense of delight, for example. There's a small application of gravity in plants that can sense up and down and our ability to sense motion. But by and large, most biology is explained by Newtonian mechanics and fairly straightforward physics. But so, I don't think it's that. I don't think it's, you know, for example- I think you can get an awful long way with nineteenth Century physics in modern biology. But nineteenth Century physics, of course, is beautiful. And the interesting thing about it from my perspective is that if we really want to understand something, a way of describing understanding is to say that when you understand something on some level, you can somehow connect that understanding to the understanding at the next level, and understanding at the next level, and the next level. There are many levels of understanding, you know, all the way up to philosophy, but we understand our body in terms of the organs in it. We understand the organs in terms of the cells. We understand the cells in terms of the, you know, the signals and the organelles. And then we understand them in terms of molecules like proteins and nucleic acids and so forth. And you keep working your way down. Of course, nucleic acids are made out of atoms, and atoms are made out of electrons and protons and neutrons and- understanding, really, in one view is a way to form a description which passes in a continuous way up through these many different levels of understanding. And physicists spend a lot of time worrying about the lowest level. They don't spend a lot of time worrying on how they connect up to the next level. Some do. Condensed matter scientists worry about that a lot. Whereas particle physicists don't. Or do but do it on level which is below the level of condensed matter physicists. And by "low" I don't mean intellectually inferior, I mean in some sense, smaller dimensions and different realms of time and space. So, I think, but biophysics about is really trying to connect up life as we know it to the mechanisms and motions of the molecules that are most responsible for life. And those molecules are proteins, nucleic acids, and lipids and so forth. And so how do we understand that? And those stories cannot be told in most cases by just biologists. They can't even be told by biochemists. I think ultimately, they need to, you know at some level, they need to be told by biophysicists. And so, what part of physics do I use? Well, there's a whole branch of physics which is really about measurement. So, we know what theoretical physicists do. But most experimental scientists use various tools of measurement to observe nature. Ranging from, you know, the radio-telescopes and telescopes that astronomers have all the way down to, you know, microscopes and below. And what physicists know that a lot of these other scientists don't know is they know about how to make measurements. How to do the statistics properly. How to do the data analysis properly. How to handle fluctuations properly. When to believe your numbers, when not to believe your numbers. They're the tricks of the trade of the experimental physicists which I think are invaluable and these are the tricks of the trade that really help biophysics get farther, say, than a biochemist gets or that a geneticist gets. So, I mean, these days, there are mathematical tricks. For example, a computer scientist knows, or mathematicians know. And they're being applied like gangbusters these days to the analysis of biological information. Bioinformatics. So there's an example of a field that's got nothing to do with biophysics, but where increasing knowledge about genes and gene control is being provided by people who can run computer programs or develop computer algorithms or have statistical analysis techniques that allow them to derive information from this, you know, gigabytes of sequence information, that we wouldn't have otherwise, and that'd be something that a traditionally-trained biologist would be absolutely incapable of doing. In the same way, there are things that a biophysicist can do with biological information which a traditionally trained biologist is also absolutely incapable of doing. From the early on, for example, you know, structural biology, crystallography, and NMR. All the structures we know of proteins were derived by people who didn't start off in biology, they all started off in- in fact, Blackett and others got the Nobel prize for developing crystallography, not for- and which ultimately was used in biology, and there are Nobel prizes that are mostly in chemistry, in fact, for doing this. Chemistry is kind of strange because, you know, there's not a lot that's chemical about using x-rays and crystallography to discover positions of atoms in molecules, right? What chemical about that? It's a purely physical technique with purely physical modes of analysis that involve mathematics. In fact, the kind of mathematics that most physicists are very comfortable with. So. in a similar vein, and this I think getting to the answer to your question, while the physics that we use is by no means arcane or difficult physics. It's not gravitational tensors and it's not multidimensional string theory. While the physics is really quite straightforward and simple, it is nonetheless being used with state-of-the-art instrumentation and state of the art analysis and data techniques to get insights from a physical perspective. About the molecules of life. One example, which I would cite immediately, is in statistical mechanics. So most of us have gone through a degree in physics have and to take stat mech, and one thing that you might recall from your stat mech classes is that any time you were given a problem, usually told to solve it adiabatically or quasi-statically or reversibly, and all these words refer to the fact that we've known for a great many years that when you start to do things well away from equilibrium, it's very hard to write down the thermodynamics of the situation. And that non-equilibrium thermodynamics is a very difficult subject all on its own, with very few solutions. And you only get those solutions when it gets struck with equal sines in the thermodynamic equations. However, as late as, what is it, in the 1990s, Chris Jarzynski at University of Maryland solved Jarzynski's equality, or Jarzynski's equation, in which he showed amazingly that you could derive the equilibrium free energy for a reaction by measuring transitions and their reaction far away from equilibrium. But if you measured enough of them, and if you weighted them appropriately, they have to be exponentially weighted, the average of the exponential of the work performed is equal to the exponential of delta G, the equilibrium free energy. That's a result you can write down in one line, it's a one-line equation. It looks totally simple. Looks like anybody, any freshman could derive it on the back of an envelope. Actually, it requires many, many pages of very hard work to derive despite its disarming simplicity. And it's made possible entire field of endeavor in biophysics. Because in biophysics, if we want to ask when we fold a protein, how much energy is associate with that fold, when we pull it apart, we're ripping it apart with forces that are way away from equilibrium, and we watch it snap back together again. Again, it's way away from equilibrium, and there's no way we can do this quasi-statically. There's no way we can do this reversibly. No way we can do this adiabatically. But Chris showed us that if we make enough of these measurements and make them accurately enough, we can actually derive the equilibrium free energy. And there have been a number of PRL papers by people like Gerhardt, at UCSD, these are all theoretical physicists. There have been a number of papers which have shown how we can apply Jarzynski's formalism; there's another formalism called the Crooks formalism. We can apply these formalisms to the problems of protein folding, the problems of RNA folding, the problems of DNA folding. So, here's an example, a beautiful example, of how new physics, I mean this is physics from the 1990s, after all. How new physics, I think it was '99 in fact, how new physics can actually be used to solve interesting problems in biology. So, the connection is still there, even though it may not involve, you know, the kinds of sexy physics you hear about from, you know, cosmologists or form string theorists. So, the two answers to your question, which is what aspects of physics are most applicable to biophysics as I practice it, the answer is there's a lot of stat mech in what we do. That's number one. And number two is it's not so much the complexity of the physics, per se. It's the complexity of the physicist. It's the complexity of the techniques we bring to bear. The experimental techniques we know, the data analysis techniques we know, and again, back to use this word again, the mindset we bring to the problem that really makes it physics.
Well, Steven, as a capstone to this amazing and epic conversation, I want to ask you a forward-looking question. I'll make it a multi-part, get my money's worth. Where do you see, and this is regardless of whether you will continue on as a practicing experimentalist or you'll be looking from the sidelines. However, that plays out, and I wish you the best in whatever that means for you personally.
Where is single molecule biophysics headed? Where do you want to see it headed? And do you think that those are one and the same thing? And if not, to what extent are you in a position to help shape the future of the field in a way that you see that it should be going, and it might not if you did not have that influence?
Well, let me take the last bit first, which is that I think it's fine where it's going. I don't think it needs me to shepherd it. And it's certainly not spinning off in the wrong direction, so I don't see a compelling need for me to get involved and help guide it into the correct future direction, against, God forbid, it spinning off in the wrong direction. And I think anybody who tries to guide science like that is a little bit foolhardy, because you know you can't just imagine where things are going, and you can never predict what next new serendipitous discovery might not lead to something else. So, I think it's always a bad idea to try to guide science off in direction. I know branding agencies try to do this all the time (laughter). And I have to say that when people write up their five-year retrospectives on where they want with a grant, it's only a tiny fraction of the time that they actually want to go in the same direction as they proposed in the original grant proposal. Some of that is true. If they didn't do at least a little bit of it, they probably wouldn't get the next grant. But on the other hand, a huge amount of the science, an unappreciated amount of the science, that we do is serendipitous. It's based on some new lead we just got yesterday, or some new idea we just had. Or something that fell into our laps as a result of our last measurement. And that's entirely appropriate. That's the scientific method. And so, if we chart a path too far into the future, we do so at our own peril. But the, so the third part of the question, I don't feel a compelling need to, you know, guide science in any particular direction. And I think the field is doing just fine and will probably do just fine without me. Although, of course, I would much rather do it with me. But that's, it is what it is. Now, in terms of the general field of biophysics, I think the field is in a rosy state right now. I sort of answered this earlier, but the fact of the matter is that as evidence of that, the meeting that I hold every two years has blossomed. I now co-run it with Thomas Perkins at the University of Colorado. We have mailing lists of order of 1500 people who are interested in this meeting. We can only take 110 or so and fit them in the auditorium at the Aspen Center for Physics. So, we're over-subscribed and it's going really well. Professional societies now consider single molecule biophysics to be an actual topic, that didn't exist except in my mind's eye fifteen, twenty years ago, so the Biophysical Society has this, there are awards now in single molecule biophysics, which didn't use to exist. So, the field is in a healthy state. I think it will continue. And the first part of your question is, where is it going now? And I think it's probably going in the same directions that I was going, but it's also ramified out in other ways. So, if you can do single molecules, then you should-- single anything suddenly becomes interesting. On the sequencing DNA side, there's now single molecule cell sequencing. So instead of sequencing an organism, you can sequence just a single cell from their body. And why would you want to do that? Well, some cells are, you know, cancer cells and have aberrant genomes and you might want to learn about that. But also, it turns out our immune system splices DNA, and every time we make an antibody, we're making something that has never existed before in the history of our organism, and possibly in the history of our species. But so, we splice DNA and make antibodies on the fly that have to work against things like COVID. The mechanisms by which we make these are not well-understood, and each cell is a little bit different and so people are very excited now about being able to have a sample that's so small that it's the genome complement from just one cell. That means there's just one DNA molecule. Right? There are twenty-three chromosomes, right, forty-six actually because they're duplicated. So basically, in principle, every gene is present twice, but only twice. And some of those two may be a little bit different because, you know, the strain from your mother and the strain from your father might have crossed over, make slightly different things, but the bottom line is that a single cell is essentially- if you can do single cell sequencing, you're really talking about single DNA molecule sequencing, and (inaudible 1:03:12). So, things are becoming so sensitive now that it's possible to contemplate that. People are working in that direction. Not me, but that's a field that's going in. That has the potential to revolutionize some aspects of medicine, right? So, we were talking before about what's going to be good for mankind. I think the ability to do this is important. One of the deep questions in biology that I alluded to earlier was this question of gene control. The ultimate expression of gene control is what biologists call developmental biology. So how do I grow from an embryo into a complete organism? Why does my nose know to stop here and not go out like Pinocchio's? Why doesn't Trump's nose grow out? This all has to do with the fact that these, all my cells have instructions and they're regulating and if we really want to understand biology, then simply sequencing our DNA is not going to be enough. Because every cell in my body has the same DNA, and yet every cell in my body is acting differently. And we're back to nature and nurture questions. Is it just the background of the cell, the experience it had in the fetus and growing up, and what stitches it was next to that caused it to be the way it is? Or is there something like a clock which is ticking on in the cell and changing its behavior as a function of time, so it's predestined to do certain things? The answer to that question, by the way, is both of those things are true. And how do we get at them? And how do we get at developmental biology? And you know, that's an entire field and people have been working in it for years. But I think single cell sequencing and what's called transcriptomics, which is determining the sequences of all the RNAs, not just the DNAs. These are the kinds of things that are revolutionizing molecular biology today. And they all point in one direction, and that one direction is the inevitable progress towards single molecule answers. Not ensembles of molecules. And you know, at this point it's almost a cliché, but you know, when single molecule biophysicists get up and give lectures, they usually start their lecture with a statement about why it's important to study single entities. Now, physicists scarcely need to be convinced about this, because that's their inclination in the first place. But the fact of the matter is, if you can only measure ensemble averages, you're inclined to make some mistakes. Or come to some wrong conclusions. One analogy that I use on a slide, is I show a ship. I show a map of the world, and I show the route of a ship that would travel from, for example, New York to San Francisco. Now, the ship is small enough, it goes down, it takes the Panama Canal, comes back up the other side. If the ship is too big, it's got to go around Cape of Good Hope- sorry, Cape Horn, what am I saying? It's got to go around Cape Horn and South America and then come all the way up the other side. So, I ask the audience, "Well now consider the average path taken by all ships traveling between New York and San Francisco. Well, the average path is some mixture of things which travels right through the center of the Amazon jungle, and winds up in the mountains of the Andes, and comes down through the Atacama Desert, which is the driest place on Earth, before it finally hits water and makes it up to San Francisco. So, if you can only measure average paths, you might be inclined to come to the wrong conclusion. And ensemble averages can be misleading if you don't know what you're actually dealing with as single entities. Again, this is- it's the instinct of a physicist to instantly realize, of course that's true. But you'd be surprised, because biochemists, you know, to this day still work with Avogadro's number of molecules and these interactions. And it's partly because that's what they have to do. These things are not available to them at this level. The techniques they use don't have the sensitivity to reach single molecules and haven't had that for years. And it's only been in the last twenty to thirty years that our measurement techniques have become so sensitive that we can even contemplate doing these kinds of things. Measuring the displacement of a single protein at the angstrom level. Measuring the concentration of a DNA molecule, at the level of one DNA. Measuring the transcripts that come on, measure at the level of maybe a mere handful of such transcripts. So, these are technologies which are then brought to us by biophysicists. The other Nobel prize was super resolution microscopy. Again, brought to us by physicists. You know? Folks like Stefan Hell and Xiaowei Zhuang, who pioneered these methods of doing this, and these microscopies are all based on physics. It's nineteenth Century physics, okay? But it's physics. And there's still a lot of mileage left in nineteenth Century physics.
Well, Steven, I don't know.
I don't know about you, but I'm tired (laughter).
There's only one word I think that can describe this, and that is epic. And you know, when we start these conversations, I never know what I'm going to get, and you delivered in a big way. So I want to thank you for your time and your generosity, sharing all of your perspectives with me, and you know, to state the obvious, this will eventually be a tremendous addition, both to our collection at the Niels Bohr Library, but also to the historical record in general. Particularly on the sociological side, your comments about what universities are really there to do. And I can see that really resonating, and I hope that to the extent that this is a cautionary tale, it's one that gains some traction and that some people are even held accountable, or at least are required to think about what it is that they're there to do. And I think that's tremendously valuable, and I really appreciate how honestly and boldly you shared your perspective with me. You know, throughout, but in that in particular.
Well thank you, it's been an unalloyed pleasure speaking with you. You not only asked great questions, but I'm amazed at your ability to anticipate where things are going, because I sense a resonance.
Well, it's what I do for a living, so I try to be good at it. So-
Well you sure are. Anyway, no one has kept me talking this long except my wife Kathleen when we were first dating (laughter).
I'll take that as a compliment (laughter).