Steven Block

Zierler:

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.

Block:

It is my pleasure as well.

Zierler:

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

Block:

All right. I suppose my full title would be the Stanford W. Ascherman Professor of Sciences at Stanford University. I hold appointments jointly in the Biology and Applied Physics departments. I’m a biophysicist.

Zierler:

And not to put you on the spot if you don't know, but can you tell me a little bit about Ascherman?

Block:

Actually, I really don't know much about him. He was a medical doctor who was educated at Stanford University and maintained strong ties to it. To the best of my knowledge, left in his will a provision to finance two endowed chairs at Stanford University. Today, there's one Ascherman Professor in the Medical School, and there's another in the School of Humanities and Sciences. I hold the current 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 other universities, does not furnish their endowed chairs with a healthy allowance that can be spent on various things, such as paying for a postdoc or a graduate student, or on travel, or on some special equipment. In fact, we only get a meager allowance of $5,000 a year, which scarcely pays for the beer and pizza in my research group. That's all. In practice, it's mainly an honorific title.

Zierler:

Uh-huh. Well, let's take it right back to the beginning. Tell me about your parents and where they came from.

Block:

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 Ashkenazi Jewish on both sides of my family. My mother's family fled Hitler, first to London and then eventually to New York. All my relatives who remained in Germany were exterminated by the Nazis. My mother was all-too keenly aware of this. She had played the piano, and she had to learn how to play the accordion on short notice, the way that the family got out of Germany was to pose as a band of traveling musicians. My grandmother had been a singer: she was a soprano. She eventually sang in places like the chorus of the Metropolitan Opera in the United States. And she had given some solo recitals in Germany. So, she was the lead singer in this fake band.

Zierler:

What was your mom's family's socioeconomic status in Germany?

Block:

They were thoroughly assimilated Jews. They were scarcely religious at all. They did, of course, practice Judaism, but like a lot of Jews whom I know, including myself, they rarely went to temple, except on perhaps Yom Kippur or Rosh Hashanah. And that was it, for the most part. They considered themselves to be German, first and foremost. And like so many of the intelligentsia, upper-middle class, and bourgeoisie Jews in Germany, they considered themselves an important part of German culture. The Nazi era came as quite a shock to so many of them.

My grandfather -- my mother's father -- was a glove manufacturer in Würzburg, Germany. He eventually made it over to the United States before the war, but unfortunately passed away of a heart attack soon thereafter. They smuggled a lot of the family fortune out into the United States. There's an amazing story behind that, which is my grandfather would take the train into Switzerland through Basel. If you've ever been to the Basel train station, which lies astride the border, you know that there's a long stretch of track. There's a Basel station that's on the German side, and another Basel station on the Swiss side, separated by perhaps a hundred yards of track. What would happen is that they would let the passengers off on the German side, they'd go through border security, and come out on the Swiss side. They and their luggage would sometimes be searched. So, to prevent it from being discovered, he would take a satchel of money and shove it in the “accordion” pleats that were between the rail cars in the German trains. Sometimes, they would use the same train and simply advance it down the rail, but other times they would swap out trains. So, he didn't dare send all the money at once. He would have some 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. He did this on a number of trips.

And at some point, and I'm unclear on the details of this, and I think it may not have been during one of these dangerous passages, but at some other point, he was rounded up by the Nazis, and he was thrown into the concentration camp at Dachau, which is just outside Munich. But amazingly enough, he actually managed to escape Dachau with the help of an S.S. officer who recognized him. This was an officer whose life, apparently, my grandfather had helped to save during World War I. He had received the Iron Cross fighting on the German side in the First World War. And it was later to be his ticket out of Germany. My grandfather had to get forged papers indicating that he'd never been arrested, and eventually he was able to pass through the borders and join the rest of the family in London. Eventually they all arrived in New York City. Coming here, they also carried a steamer trunk with a false bottom, which they’d filled with valuable German camera lenses, among other things, that my father could sell for cash, to help get them started in America. They were able to emigrate only because we had some cousins already here in the States who’d arrived much earlier, and had settled in San Francisco.

Zierler:

Woah. (laughs) That's amazing.

Block:

This is the sort of stuff of which movies get made.

Zierler:

Yeah.

Block:

And this is the story that got passed down through my mother, who arrived in the U.S. in her early teens. She was, however, extremely reluctant to talk about what had happened in Germany for many, many years. My mother passed away just a couple of years ago, so we’ll never know those stories in adequate detail, I’m afraid.

Zierler:

Right. But what you do know, you got from your mom?

Block:

That's right. Also, a little bit from my grandmother, Irma, the opera singer. Apparently, she had quite a bohemian youth. Her husband owned a motorcycle with a sidecar, and she'd go cruising around Germany in that sidecar. So, I’d say that was pretty active. My mother's side of the family is rather musical, and my lifelong interest in music, I suspect, may come from that side. My father's family is also Ashkenazi Jewish, but they’d arrived in the United States much, much earlier: probably around the turn of the 19th Century, although the details of that are not well-known to me -- nor were they to my father, for that matter. His family first settled in New York, and eventually in nearby Newark, New Jersey. It was in Newark, in fact, where my mother and my father met one another. They both attended the same high school: Weequahic High School. That's the same high school that the author Phillip Roth attended, by the way.

Zierler:

I was going to ask, yeah. (both laugh)

Block:

And interestingly enough, my parents didn't actually manage to meet in high school, even though they graduated in the same year. They met a bit later on, when my father was a student at Columbia University. But my father's family hails from the East European shtetls, from the small towns in a place that used to be called Galicia.

Zierler:

Right.

Block:

It’s located in what was called the “Pale of Settlement,” which is today part of the Ukraine and Poland. I can tell you that the comparatively well-off German Jews pretty much looked down on the impoverished Galitzianers!

Zierler:

Of course, right.

Block:

The German Jews were bourgeoisie: they were established; they were assimilated. The Galitzianers were poor folk from the sticks. And so, maternal grandmother was not exactly thrilled to learn that my mother was going out with my father, once she found out. My paternal grandmother also has an interesting backstory. She was divorced, which was rather uncommon in her era. The first person she married, a guy named George Block, who was my paternal grandfather, served in the 10^th Mountain Division. These were the U.S. ski troops in World War II, and they trained at Camp Hale in Colorado. That grandfather eventually helped build the historic toll road up Mount Mansfield in Vermont, near Stowe. He became something of a ski bum, but before that term was invented! In fact, he was such a ski bum that my grandmother eventually divorced him, and he went off to pursue his other interests. Which may be why skiing is such a big thing in my family.

Both my mother and father were skiers, too. In fact, they founded the Newark Ski Club shortly after World War II, mainly to help finance their own ski trips. Eventually, many years later, they were to buy a house in Aspen, Colorado, where they lived for some 50 years. They first had me out skiing when I was just three years old. I wound up going to first and second grade in Italy, and a good part of that time was spent in Cortina d'Ampezzo, Italy, in the Dolomites, where I really learned to ski. By the age of about five or six, I got really good at it. I won my first ski race when I was six years old (laughs). Truth be told, I may have been the only racer in my age category, however (both laugh).

But back to my father's family, after that digression. As I was saying, my paternal grandmother was extremely bright, but she never finished high school. However, she was one of these people who could polish off the New York Times crossword puzzle in a matter of minutes. She had two brothers, both of whom went on to become prosperous lawyers. As I said, she divorced her first husband, who was my grandfather, and she re-married a Catholic, which, in that era, was considered to be an outrageous act. He was a window washer, but he eventually his company got contracts for washing windows in places like the Empire State Building. So, his Newark-based company did very well. That grandmother spent the latter half of her life cruising the world like some sort of incarnation of Auntie Mame, collecting very loud and expensive jewelry from European shops. She was especially fond of the goldsmiths on the Ponte Vecchio in Florence, Italy, as I recall. She loved to travel, and she was a larger-than-life personality. She was very, very vocal and often outrageous, in a lot of ways. On her side of the family, she had two sons, my father Martin, and my uncle Robert. Both of them were smart, and both went on to become physicists. My father became a particle physicist, trained at Columbia, and my uncle became a nuclear reactor physicist, trained at Duke. Today, my uncle Robert is a dean emeritus at the Rensselaer Polytechnic Institute. He is still publishing in 2021, on neutron cross-section and measurements. My father eventually wound up at Northwestern University, where he chaired the Physics Department for a time. His first assistant professor job was at Duke University, and my family was there for a number of years. I was born in Duke University Hospital. Eventually, as I said, the family moved to Northwestern in Evanston, Illinois, where I attended high school. But all the while. my father was busy saving money so he could buy the family a second home in Aspen, Colorado. My parents bought our home in Aspen back when you could buy a house in what is, today, the tony West End, for on the order of $40,000.

Zierler:

Wow.

Block:

That was back when most of the West End houses were dilapidated and falling down. They were mostly old Victorians that hadn't been kept up since the collapse of the silver market in 1893, which had turned Aspen into a ghost town, until it was revived by the ski boom of the late 1950’s. The West End roads were dirt, not paved, and it was a very different place from the glitzy Aspen of today. So, as I grew up, spending parts of winters and most of summers in Aspen, I got to see the town undergo enormous change. As you know, Aspen is not only a great ski area: it is also the home to a major music festival during the summers, and home to the Aspen Institute and to the Aspen Center for Physics, which is very active in the physics world.

Zierler:

Oh yes.

Block:

So my father was there, virtually since the founding of the Aspen Center for Physics in the early 1960s. It had been only in existence for on order of one to two years at the time he joined. Much later on, in 1985, my father was eventually responsible for founding the annual series of Winter Conferences, which have thrived, and are held to this day at the Aspen Center for Physics.

Zierler:

Of course, because that's when you have to ski. You have to do it in the winter.

Block:

That's right! Of course, the Center has had a very active program in the summers for many, many years, but the executive officers of the Aspen Center for Physics had been very reluctant to start a winter program, partly because during the high season, the Aspen hotel rates are very high, and they thought that the physicists wouldn't be able to afford it. But my father had noticed that (at least back in that era), there was actually a short period of “low season” in the middle of January. This happens because families with children would come out to ski over the Christmas holidays. On the other hand, folks who were freer to travel whenever they wanted, namely, the young, the independent, or the wealthy, would tend to come out in February and March, when snow is at its best. That meant that the middle of January was generally a low point, even though it was technically during high season. My father was able to negotiate bargain rates at some local hotels during that period, and this proved to be highly successful. They started, first, with a single winter physics conference on particle physics, my father’s field. But that quickly snowballed. There are now as many as eight or even nine different physics conferences held every winter, on a variety of topics ranging from biophysics to cosmology. Alas, there's no longer a low-rate point in Aspen’s high season: the popular Winter X-Games pretty much took care of that! The Physics Center now books hotel space throughout the entirety of the ski season. But somehow, the physicists come from all over the world, and they’re able to afford it. It turns out that giant meetings held in many big cities at convention centers cost about the same, once you factor in all the costs.

Zierler:

Do you know who your father's advisor was at Columbia?

Block:

Yes, he was I.I. Rabi. Well, only sort of. Technically, my father’s thesis adviser was Bill Havens, but my father didn’t get on especially well with him, and he looked to Rabi for a lot of inspiration and advice. My father wound up helping to design the magnets for the Nevis Cyclotron, which was the most powerful particle accelerator in its day, at around 400 MeV. But that’s less than half the rest mass of a proton!

Zierler:

Oh wow.

Zierler:

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?

Block:

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 mostly by trying to escape my upbringing, not clinging to it.

Zierler:

Yes. (both laugh)

Block:

This is ironic, of course, because today, I consider myself to be a physicist in so many ways. For example, I have come to run one of those Aspen Winter Physics Conferences of which we spoke, myself. In fact, it's the longest-running single conference in the Aspen winter series: the Single Molecule Biophysics conference, which was started in 2001. Here we are in 2020, and it's still going. I grew up with physicists all around me. My parents were rather social, and my mother was a superb cook, and so my father was fond of bringing all manner of colleagues home for the evening, wherever we lived – and we lived in a lot of places. I've spent time practically everywhere in the world where there's a major particle accelerator. Except for Dubna, Russia, that is. I spent a good bit of my youth in Geneva, Switzerland, because my father spent more than ten years working on experiments working, on and off, at CERN. I've spent time in Evanston, Illinois, which is near Argonne National Labs. Evanston is also quite near Fermilab, which was built later. I spent time as a small child out at Brookhaven, Long Island, and in Berkeley, California, home of the Bevatron, which was one of the first big particle accelerators, built to achieve a billion electron volts, and produce an antiproton. So: Brookhaven, Berkeley, CERN, Argonne, and Fermilab, all figured into my youth. Oh, and SLAC.

Zierler:

I wonder if you've ever compared notes with Persis Drell, for who was more drenched in physics growing up?

Block:

Oh, yeah, I know Persis! But I met Persis much later, from the time I when I delivered the Hans Bethe Lectures at Cornell University. I was deeply flattered, in fact, to have been invited to do this, because it was relatively early in my scientific career. This was in the Spring of 2000, and I met Persis Drell there: she was on the Cornell faculty at the time. I also had the opportunity to meet and interact with Hans Bethe there before he died, which was a thrill for me. I also knew Persis in another way, which was through her father, Sid Drell. He, of course, was a famous particle physicist who’d served as the Deputy Director of SLAC for many years. Sid Drell was a major player in a consulting group called JASON, which advises the U.S. Government. I guess we'll get to this later. I actually knew Sid much better than Persis, and I interacted with him over many summers, where we both worked together in La Jolla for JASON. So, we've had a chance to compare notes. I grew up with famous physicists all around me. I met Richard Feynman, for example, when I was very young, and I met Murray Gell-Mann, too. I met Georges Charpak, who later became a Nobel laureate, as did these others. In fact, Georges and his family loved to ski, and so did mine, and we would sometimes join them on ski trips, or meet up at the same ski resorts, especially in Val D’Isère, France. It was Georges Charpak who first took me down the Vallée Blanche at Chamonix, back when I was a teenager, or perhaps in my early twenties. I have all kinds of memories of the famous physicists I met in my youth.

Zierler:

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?

Block:

Although I was born at Duke University in North Carolina, my parents left relatively early in my life, so I didn't pick up much of a southern accent. In fact, my accent, insofar as I have one at all, has distinct tinges of New York City in it. 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/marry", all sounding alike. So, I have some linguistic influences from New York, which is pretty ironic, because I've never lived in New York in my entire life! However, I did live in the north of Italy. My father went on a Guggenheim Foundation Fellowship to Italy when I was five and six years old. There, he worked with a physicist named Gianni Puppi, in Bologna, at the University of Bologna. But I think my father quickly grew bored with what was happening in Bologna, so he decamped the whole family and moved us to Cortina d'Ampezzo, up in the Dolomites, for the winter and spring. They enrolled me and my sister in the public school there.

There are some interesting stories from that time as well. Cortina had been the site of the 1956 Winter Olympics, as you probably know, and in those games, there was this incredible Austrian skier from the nearby Tyrol. A lot of the people in the Dolomites speak German, rather than Italian, as their first language, and most are bilingual. That year, an Austrian named Toni Sailer won all three of the gold medals in Alpine skiing. This inspired the folks in Cortina that they might be able to nurture an entire generation of ski athletes in their village. So, what they did was transform their educational program. The local kids would go to school in the morning until about noon, whereupon school would break for the day, and they'd all go to ski school in the afternoon. I was part of this educational program, and it was just wonderful. (laughs) I managed to get a winter's worth of intense ski training at the age of five, thanks to it.

Another unusual (to me) aspect of the school system in Italy is that there was really no separation of church and state. And, of course, it's all run by the Roman Catholic Church (Pope John XXIII, who was much beloved, died when I was in school in Italy, and I still recall the huge outpouring of grief.) Several times a week, the local priest would come into school to teach us our catechisms, and he would hand us out things that, for all the world, looked like baseball cards, except that they'd have a picture of Jesus on the front, performing some miracle, perhaps the loaves and the fishes, or walking upon the Sea of Galilee. And on the back were all these empty little heart outlines. The idea behind these cards was that every time you said a prayer, say, an Our Father or Hail Mary, or did some good dead, you would take your colored pencil set and you would color in one of those empty hearts. The cards were then collected by the priest at the end of each week. Well, my parents had given me this fabulous colored pencil set, from Caran d'Ache. This was the famous Swiss colored pencil manufacturer. These sets were to Italian kids what those giant Crayola crayon sets are to American children. You get this inspiring box loaded with so many brilliant colors. But there was no opportunity in the regular classes to use all those colors. So, I would use them to color in the hearts on the back of the miracle cards. I would color them with rainbows or stripes or dots or paisley, and I used practically every color in the set that I could. And of course, I handed in the cards every week, fully endorsed. This was--

Zierler:

Now, were your parents secular, so secular that they weren't bothered by this? Or were they just Jewish enough where they were horrified by this?

Block:

Evidently, they weren't bothered by this at all. And the story continues, as you'll see. None of the Italian schoolkids, of course, would dare to do this, because they thought they would spend God-knows-how-many years relegated to Purgatory for each falsely filled heart. My mother would go out shopping in the village every day, as you would in Italy, and she would go to the local trattoria or salumeria or groceria to pick up our food. One day, she ran into the local priest, who came up to her and said, in essence, "Your son must be bound for the priesthood. He's handed in all these completed cards. And 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 my son is a smart aleck. He just learns these things. But he learns lots of other things, just as well. It has nothing to do with religion. As for those colored marks, he's just having fun with his colored pencils." She was being honest, hoping to disabuse the priest of any notions of my possible sainthood. But in fact, the priest just shook his head -- he couldn't quite wrap his head around it. He decided I had to be all-the-more holy, to be growing up in a background of Jewish devils like this, and that this was somehow a transformation on my part. My mother went away shaking her head, too. She’d tried to explain things honestly to him, and to rat me out (which I deserved), but it hadn’t quite worked as she expected.

So, by the end of our stay, I came back from Italy well-schooled in both skiing and Roman Catholicism. Oh, and my mother had another difficult encounter, this time with my schoolteacher, because I'm left-handed, and they wanted to train me to write right-handed. Back in those days, you literally dipped your pen into an inkwell. With some persistence, my mother succeeded. She got my teacher to agree to teach me to write left-handed, which is something he’d never done before. He taught me to hold a blotter under my hand as I moved the ink pen across the page, so I could blot the wet ink as it passed underneath my left hand, going from the left to right. So I learned to write with a blotter. Actually, I learned quite a lot in first grade in Italy, in addition to how to ski and about religious practice. In the first grade in Italy, you not only learned addition and subtraction, but you also learned multiplication and even long division. So, when I returned to the United States to Durham, North Carolina, having been taught first grade in Italy, I was already ahead of the curve.

Zierler:

And the classes were in Italian or English?

Block:

This was Italian public school, so everything was in Italian. I was thrown in the deep end of the pool by my parents so I would learn Italian. So, I learned how to read and write in Italian, before English. I learned to speak Italian, too. I still speak some Italian to some extent, but with the vocabulary of a five-year-old (both laugh)! Alas, I haven't spoken it for a good many years, and so – fast-forward to the days of my honeymoon, which was in 1986 – my wife and I traveled to Italy, and the language came flooding back to me. It was amazing. I could scarcely speak it, but I could understand nearly everything that was being said to me. And of course, the Italians are so very generous if you even attempt to speak their language: they’ll go out of their way to help you. This, in contrast to the Swiss Romande and the French, by the way, when you speak in halting French, they will do nothing of the kind. But I also learned to speak French in my childhood, a bit later, and I can still speak it to this day, having been placed in public school in Geneva, Switzerland. But I’m getting ahead of myself: back to the Italian story: My family returned to Duke, in Durham, North Carolina, and the public school administrators there wanted to put me back into the first grade, even though I should have been in second or third grade at that point, on the grounds that I couldn't read or write English. Which was absolutely true. Italian, as you know, is written phonetically, so I would pick up some English text and I would start reading it as if it were phonetic Italian. That was pretty embarrassing. My mother had a big fight with the school board about my placement, and they eventually moved me up into the appropriate grade. And I soon caught up. So, that was my time as a child in Italy. I had a fabulous experience learning to ski, and I got pretty good at that -- good enough to teach skiing as a teenager, and good enough to earn my ski teacher certification when I was in college. To this day, I'm still an avid skier.

Zierler:

So when did you move back to North Carolina?

Block:

So we moved back to North Carolina, this would have been about 1960 or thereabouts. We were in Italy in '59 and '60, maybe it was '61.

Zierler:

And your father was on the faculty at Duke?

Block:

He was on the faculty at Duke University, in the Physics Department, that's right. My father's contributions to particle physics were several-fold. He also had an interesting personal story. He was an experimentalist, and he was interested in elementary particles. Back in the 1950’s, lots of new particles were being discovered, left and right. This was just before Murray Gell-Mann's so-called Eightfold Way description, and the later, the understanding of quarks. There seemed to be a new particle every month that was being discovered. My father was one of the co-discoverers of the eta meson, which is a three-pion resonance. He was also the inventor of the helium bubble chamber. The hydrogen bubble chamber had been invented in 1952 by Don Glaser and others, and had been used very successfully as a particle detector, and to study particle reactions. The main advantage of the helium bubble chamber was that it offered, in essence, alpha particles as targets (helium nuclei), rather than protons (hydrogen nuclei). And so, he built the first helium bubble chamber. This turned out to be a huge experimental challenge, because as you cool helium, it becomes superfluid, and therefore very hard to contain. A challenge of building the helium bubble chamber was to be able to get seals that were sufficiently tight, so that you could expand and contract the helium rapidly, to produce the bubbles, and yet not have it leak completely out of the chamber. He eventually used indium metal to form a gasket seal, which is something that’s still used to this day. All that was just being worked out at the time. So, he built the helium bubble chamber, carried out some pioneering work with it, and largely on the strength of that work, I think, was recruited as a department chair to Northwestern University, from Duke. So, for my high school years, we moved to Evanston, where my father continued his experiments with the helium bubble chamber at Argonne, and then eventually, using still other detectors, at Fermilab.

Zierler:

So your teenage years were in Evanston?

Block:

They were. It was a time of great tumult. Much as today. It's ironic, because as we're speaking now, there's the funeral of George Floyd taking place; I was watching it earlier on television. When I was in Evanston, it was during the Vietnam War. I was very politically active and marched against the war while in high school. I also marched, this time more successfully, for the adoption of an equal housing ordinance in Evanston, with activists based in AME Church.

Zierler:

You were too young for the draft, though.

Block:

Yes and no. I was too young for the draft in high school. But back then, by the time I was ready to graduate from high school, the government has established a number drawing, based on your birthdate, for the draft lottery. My birthday is October 4^th, and that was, if I recall correctly, it was something like number 66 in the draft. That's a fairly low number, giving me a high probability of being drafted. I didn't want to go to Vietnam, I didn't think that our involvement in Vietnam was right: I was adamantly opposed to it, in fact. So, I eventually wound up moving to Oxford University, in England. I guess I’m getting ahead of myself again, but I moved off to England, at least partly, to avoid the draft. At the time, deferments for college students still existed, but the rumor was that Nixon was soon going to get rid of these deferments altogether. So, one of two things was going to happen. Either the U.S. was going to get out of Vietnam, or the war would continue, the student deferment would be abolished, and I’d quickly be drafted. Against that eventuality was one of the reasons why I went in fact to Oxford. There were several other reasons as well. We'll get to those. But I was actively against the war, and in fact, before going to Oxford, I spent one year at the University of Washington in Seattle. During that time, I was arrested during an anti-war demonstration. I was thrown into jail for the first time in my life on a trumped-up charge: allegedly, for throwing a rock at a passing police car, which missed. But I hadn’t thrown a thing. There had been members of the Seattle Tactical Squad dressed in plain clothes, interspersed among the demonstrators, and they were simply rounding up all the folks whom they thought might be leaders and charging them, often falsely. I was viewed as a potential leader, even though I wasn’t one, and I was tossed into jail and then charged. Initially, at trial, I was convicted. I then managed to find an ACLU lawyer to help me pro bono. On appeal, the conviction was overturned. So, I have an arrest somewhere on my record for anti-war activism.

Zierler:

Where were you during the convention?

Block:

During the infamous '68 convention, I was still in high school. There was the riot of Grant Park, you might recall. Mayor Richard J. Daley of Chicago, who was fond of talking to the press but always somehow managed to put his foot in his mouth, very famously said, when he was told by a journalist that the policemen were creating disorder in the streets through their actions, "The policemen are not here to create disorder. They're here to preserve disorder." (both laugh).

Zierler:

That's great.

Block:

I kid you not. You can look it up. But you know, it's pathetic, when you fast-forward half a century later to today, and we see the very same problems with our police and certain politicians. In fact, tomorrow, there will be a so-called "shut down for STEM." The academic community in the U.S. will shut down for the day to protest social inequities, and so I'm glad our interview turned out to be today, and not tomorrow, because then, I'd have to beg off.

Zierler:

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.

Block:

I'm glad to hear it! Yes, it's terribly important. Our country is long-overdue for serious change. And in some way, it's very heartwarming to see all the demonstrations that are happening, because they do take me back to the Vietnam era that we’ve been talking about. All the demonstrations in the streets ultimately had an effect, perhaps not as much of an effect as most of us would have liked, but it did change America, and we finally did get out of Vietnam. It's high time for America to change again, and I can't even contemplate what it might be like to endure four more years of racism, homophobia, anti-Semitism, fascism, and xenophobia under a Trump presidency. So hopefully, this will all change with the coming election this Fall. And there are deeper matters that the United States needs to examine itself critically about. Ironically, we fought the Civil War, but we never quite resolved it, and it's time to put that behind us. In so many ways, 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 have these abhorrent, racist views. What shocks me is not so much that Trump is President, but that he managed to get elected in the first place. It meant that there must be a significant level of support for him and his ideas in this country. Maybe not a majority, but a huge fraction. So, either we live in a confederacy of dunces, or more likely, there are lots of people in the United States that will need to be out-voted and replaced, once and for all. I think it was Wolfgang Pauli who famously pointed out that science advances “one funeral at a time.”

Zierler:

Yeah.

Block:

So, I think in many ways, social progress is very 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 die off before this country will, hopefully, come to its senses and put racism and anti-Semitism and these tribal ideas in the rear-view mirror. It's certainly not happening at the speed that many of us would like.

Zierler:

Right. Now, to get back to the parallel in the 1960s, as a high school student were you a standout in math and science?

Block:

Well, yes and no. I mean, I graduated high school after winning something called the Harvard Book Award. I guess it's the alumni of Harvard who give out this award to promising high school students in the hope that they'll apply to Harvard. In retrospect, I went to an extraordinary high school. At the time, Evanston Township High School was rated as one of the top high schools in the country. They had a grant from the Carnegie Foundation to teach, for example, Asian languages. I studied Mandarin Chinese there for two years. In high school, which was unheard-of, at the time. Although today, I’d have to say “Wǒ dū wàng-le” which means that I forgot it all. I did develop a deep appreciation for Chinese culture, though, which I carry to this day. But I wasn’t first in my class by any means. My graduating class consisted of something like 1,500 individuals, which was huge. I was probably somewhere in the top 10 or 20 of those, although I don't actually know. So I did well, and I certainly did well enough. Most of the highest-performing students in my high school had applied to prestigious east- or west-coast universities, and were going off to Harvard or Yale or Stanford or Caltech or MIT. I was a bit of a rebel, and I was active in the anti-war movement. I was interested in the Far East. I was fascinated by Asian languages, and I was captivated by Asian culture. And the other thing I was interested in, believe it or not, was the ocean. You know, this was around the time when Jacques Cousteau was making all those underwater films, and I, too, wanted to swim with the whales -- just like Jacques! So I looked around at colleges, and tried to identify one that offered an undergraduate major in oceanography, and also an undergraduate major in Chinese language, because those were my two main interests at the time. I wasn't really interested in physics at all!

Zierler:

And was that part of the rebelliousness in you?

Block:

That, absolutely.

Zierler:

Did your father, I mean, either subtly or not so much, did you feel pressure to sort of go into physics?

Block:

So here's what happened. I looked around for all these colleges and universities, and I found one that actually fit the bill. And that, it turned out, was the University of Washington, in Seattle. So I duly applied, and I got accepted to the University of Washington, and off I went for my freshman year. Newly on campus, I met with the college counselor for advice. In high school, I’d had advanced placement everything: I had AP physics, chemistry, biology, history, English, and French. And so by most rights, I should have just been allowed to enter college as a sophomore. But instead, I got lousy advice. The counselor said, "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." And they turned out to be those large lecture classes in physics and biology and chemistry and so forth. Not only that, but I learned that students were not allowed to enroll in any of the oceanography courses until they were sophomores. So, I got frozen out of oceanography in my first year. I attended a few of the large lecture classes and I was bored stupid.

I did, however, agree to take freshman physics. I’d done this in direct response to my father, who’d entreated me to the effect of, "Well, go ahead, but I just want you to take it. You don't have to love it. But it will stand you in good stead down the line." I was rolling my eyeballs and thinking, "Oh God, okay, I'll do it if I must." So I'd agreed to take physics, mostly not to anger my father. But I was still a bit rebellious. In that freshman year, I got so bored with my classes that I would often take a couple of days off every week to do other stuff. One of the things I did was to head to Crystal Mountain, Washington, which is a local ski area. I skied there a lot. And I also enrolled in a ski teacher training course, where I got certified as a ski instructor in my freshman year. I joined the UW Climbing Club, and we climbed up Mount Rainier. Or, at least, we tried to, before turning back! This was the year that they broke the world snowfall record up at the Paradise Ranger Station on Mt. Rainier. They had something like 100 feet of snow that fell. The only way you could get into the ranger station was through a hole in the roof. They dug a tunnel down and you'd enter through roof of the ranger station, which up on stilts, if I recall. So, I would go off climbing, I would go off skiing. I had a class in calculus. Again, I'd already had AP calculus in high school, so that was kind of boring. At one point my instructor said, and 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 final for her differential equations course, instead of the regular calculus final. I said, "But I've never taken a course in differential equations." She said, "I know, I just want to see how you might do on it." (both laugh)

Zierler:

And?

Block:

Well, I did take it. I still don't know if I passed it or not (I suspect that I didn’t), but it was quite an interesting learning experience. I was, in fact, able to solve a couple of the differential equations simply by looking at them and taking some educated guesses, then working backwards. But I drew a complete blank on most of the other questions, lacking any methods. Anyway, back to the physics course: I was thrown into this large, 400-person physics class, and it was just as boring as all the other classes I had. But there was one special thing about it. They gave a quiz during the first week or so. They targeted the students who did the best on that quiz to join a kind of honors section. So, I got roped into the honors section. Okay, it probably meant more work, but what the hell. I was so bored. I took the honors section. What this consisted of was that every weekend, they would invite this group of about five or ten students to the home of a physics faculty member, and you'd spend the afternoon there, just chatting with the professor. This turned out to be a transformative experience for me. I got to see the homes of the physicists (in retrospect, I was homesick, being away for the first time), which, in effect, humanized them for me. They would feed us little snacks, and we got to talk about physics in a free-ranging way. But it was very different from talking about physics when I was at my own home. When my father talked physics, he usually talked about it with his colleagues at a level that I couldn't possibly comprehend. I was effectively excluded from the conversation. By contrast, here I was a part of the conversation, and I was treated with respect. I thought this was the best thing since sliced bread. I got to know my professors better, I got interested in several new subjects, and so forth. Soon, I found myself being dragged deeper into physics, ironically, not because my father was a physicist, but rather because I was in this honors section.

Then, another big change in my family’s life came about. My father and mother went off to Geneva and CERN, for what was to become about ten years of work at the accelerator there. And if you're above a certain pay grade at CERN, the level of Fonctionnaire or above, it turns out that one of the benefits of being on their faculty is that CERN will pay for the college tuition of your children. All of which meant my expensive college education would be covered. But there was a catch, and the catch was that you had to go to university in one of the member nations of CERN. The United States is not a member nation of CERN, the European Center for Nuclear Research. So, my father wrote letters to myself and to my sister, Gail, who at that point was going to the University of Colorado, in Boulder. She's one year younger than I. My father wrote to us both and said, "Look, if you guys can get accepted into a college in Europe, it'll save us a pile of money, and besides, you might have a great experience." So, my sister spent one year at the University of Toulouse, in France. But she went for just a year, and then came back and finished up in Boulder. For my part, I wrote off to British universities out of the blue, saying something to the effect of, "I'm looking to transfer to Oxford. How do I do that?" I got back a kind of snooty letter, saying, in effect, "First, Oxford does do not accept transfer students. Second, we only accept students who have taken certain types of exams (“A-levels”). Third, if accepted, you would have to start all over again as a first-year student." And so on. I thought, what the hell? I'll take some of those exams. It also turned out that Oxford’s undergrad degree takes just three years, rather than four years. So, even if I had to start all over again as a freshman at Oxford, I would still graduate at exactly at 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 universities in the U.K. So, I sent in my application off to UCCA. And at this point, I’m pretty sure my father may have intervened, although the details of that are still unclear to me to this day. But I think he knew some colleagues at Oxford.

The bottom line is that a couple of months later, I got a letter back saying, "You have been accepted to Worcester College, Oxford, based on your application through UCCA." And so, I got accepted. But I’ve always felt awkward about that, because I think in the background, my father may have played some role in getting me in, and the last thing on Earth that I wanted to do was to advance my own career as a result of my father’s intervention. In fact, I'd spent my entire youth rebelling against that. My acceptance letter also told me about another thing, namely, that if I wished to go to Oxford to "read" a subject -- which is how the British phrase it when talking about doing a major -- I would be reading physics. I had to think about that long and hard. Despite my initial inclination to the contrary, the only thing that I really got a kick out of during my freshman year at UW was the physics honors class. So I went off to Oxford, to “read physics.” I got there, but I hadn't wrapped my head around the full extent to which I was committing myself, because I'd assumed Oxford was just like any other American liberal arts college, in that I could major in physics, but also pursue my other interests on the side. I discovered, to my shock, horror, and dismay that if you go there to read physics, physics is the only subject you take. Even the maths -- where they use an "s," -- even the maths that you take aren’t taught by the mathematics faculty: they’re taught by the physicists, and they teach 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 mostly challenged because English students receive a really good education in high school. They specialize. The British students who go to Oxford wind up not only taking A-levels, but also some S-levels, which are a level beyond that. And so, they come in extremely well-prepared, and they were, arguably, about a year or so ahead of me when I joined. This would have been in 1971 that I first arrived at Oxford.

Zierler:

Steven, culturally, what was the scene like in 1971 there? Had the counter-culture reached Oxford at that point?

Block:

Yes and no. Britain was then, and still is, a very classist society. It was the first time in my life that I really-- well, no actually, the second time in my life -- that I experienced overt anti-Semitism. A lot of people--

Zierler:

Overt as in, like, really overt?

Block:

Well, not entirely overt. Interestingly, with a last name of Block, that's not necessarily Jewish-sounding to a lot of the British, and I never made anything of my heritage. Besides, any Jewish ties that I felt were purely genetic and cultural, not religious. Not realizing that I was Jewish, I'd hear plenty of anti-Semitic expressions in otherwise polite conversations such as,"He Jewed him out of this, or that," or disparaging comments about Jews in general, as if we formed some monolithic class with a hidden agenda. Such comments would come up from time to time in casual college conversations, and while I found them offensive, I never said anything about it. It was just part of the culture of the time.

Zierler:

I wonder if your Jewish identity strengthened at that time? Just as a reaction to where you were?

Block:

Neither my parents nor I are the least bit religious. I don't believe in a god. In fact, I'm probably closer to the atheistic end of the spectrum than the agnostic end of the spectrum. Also, I find most religion to be completely inconsistent with my training, background, and thinking as a scientist. So, I didn’t become more religiously Jewish as a result of this, but ironically, I experienced my own “Jewishness” in a manner that I never had before, and I identified a bit more strongly with that, mainly as a reaction to the slights.

Zierler:

I was thinking more, Steven, in terms of Jewish pride, and like, maybe identification with Israel after 1967, that kind of thing.

Block:

Yeah. As you know, the Six Day War happened when I was in high school, and there was a strong identification with the state of Israel as a consequence. And there were marches in Evanston and so forth. I think I felt culturally Jewish, and I resonated with that. But in general, once in England at Oxford, I always had the feeling that I was the "other." But I wasn't simply Jewish: I was also “That Yank.”

Zierler:

Right.

Block:

There are a large number of Americans who attend Oxford every year, but almost all of them are there to get a second bachelor's degree, or a PhD, or a Masters. 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 a second baccalaureate degree. I was, to my knowledge, one of only two undergraduates from the United States who were actually pursuing their first undergrad degree at Oxford. So, I was a rare bird, and I think most of the cultural "other" that I experienced had nothing to do with being Jewish: instead, it had to do with being American. I can relate two stories there. The first is that I’d asked my family to send me a frisbee, because I’d loved to throw the frisbee around in the States, and there was a real dearth of frisbees in England. Some of my English colleagues were vaguely familiar with frisbees because, as it turned out, tiny versions of these had been distributed in the 1960’s inside cereal boxes in England. So, they considered these things to be large versions of toys found in cereal boxes. But I owned the so-called “Olympic-size” frisbee, and I went out there, tossing this thing around, and teaching some friends to throw. The very day in the porter's lodge – Oh, I should explain that at the entrance to each Oxford college, there's something called the “porter's lodge,” where the porter would greet you: he was a gentlemen who would check everybody coming in or out and perform various services for the college. Essentially, a receptionist. Anyway, just outside of the porter's lodge was glass case where they would post general notices. There was a note from the college bursar which said, and I remember it verbatim to this day, "Gentlemen shall not be seen with flying discs upon the quad."

Zierler:

(laughs) Okay.

Block:

So, I got banned from the Worcester college quad for throwing frisbees. And there were other Americanism that I managed to get in trouble for, too. But I was mostly known for that. The other thing that I did was play music. I'd always played a little guitar. My high school years were during the last gasp of the 1950’s-1960’s folk era, I had learned to fingerpick guitar. I also sang some Bob Dylan tunes, some protest songs, and I even played a bit of classical guitar. At Oxford, I was starved for American music, because the British were starting to listen to early versions of what later became punk rock music. In the Oxford colleges, you live in single rooms off a common staircase, and I would hear this music coming up the staircase that I couldn't really stand. I wrote to my sister, who at the time was at the University of Colorado in Boulder, and said, "You've got to send me some American music." Cassette tapes and recorders had just come out back then. She sent me two records, both transferred to cassette, that transformed my life. She’d been going out with some guy at the time who was into bluegrass music, and she sent me bluegrass albums. One was Earl Scruggs' “Foggy Mountain Banjo” album. This is, arguably, Earl Scruggs' most famous instrumental album. After the first wave of bluegrass had come a next generation of musicians who played a style known as “newgrass,” and the second album she sent was New Grass Revival's eponymous album on Starday Records, which featured Sam Bush on the mandolin and Courtney Johnson on the five-string banjo. I listened to these tapes and my jaw dropped. I thought it was some of the most amazing music I'd ever heard. I determined, then and there, to learn to play banjo. But I was also interested in folk music, and so I informed my college staircase-mates that I was going into London, to Charing Cross Road, which is the place in London where all the musical instrument stores are. I told them that I was probably going to come back with a banjo, or perhaps with a set of bagpipes, because those were also interesting to me, as well. They told me that if I came back with bagpipes, they would wrap them around my neck and throw me in the college lake. They were not joking (laughs). So, I came back with a banjo, instead, and I slowly started teaching myself from those cassette tapes. In addition, Earl Scruggs had written a book on the banjo, mostly ghosted by another famous banjo player, Bill Keith, who’d made careful transcriptions of Scruggs’ fast playing. And so, I started working out Bill Keith's transcriptions of Earl Scruggs' banjo. At first, I was just terrible. But lacking any perspective, not to mention any local competition, I formed a small band, anyway. We called ourselves the “Pheasant Pluckers.” Our name came from a British ditty, 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."

Zierler:

Wow, wow.

Block:

Now, if you get really drunk, and say that ditty, it doesn't quite come out sounding like that…

Zierler:

(laughs) I was going to say.

Block:

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 frontman for the group, because I spoke with an American accent. The lead singer of our band was a guy from Oxford and who’d been in the famous Magdalen Boys Choir. The bass player in our band was actually the lead cellist in the Worcester College symphony orchestra. He had a maiden aunt who'd died and willed him a bass viol, except he didn't know how to play the bass. The bass is tuned in musical fourths, while the cellos is tuned in fifths. He had his bass restrung in fifths like some giant cello, and he played it like that, strung backwards, if you think about it that way. There was a fellow physicist, actually, who was in my same year, who played the violin, and he had an extraordinary ear. You could play him something, and he'd say, "Wow, play that again for me." You'd play the tune again, and he'd pick up his fiddle and capture, almost note-for-note, what he'd just heard. A rare talent.

So, we had our little band, and we would play occasionally on BBC2 Radio Oxford. At Oxford, they hold balls at the end of the year, called “gaudies,” and we made quite a bit of money playing these. After that experience, I came back to the United States -- and there's a longer story there – and I started getting better and better on the banjo. This ultimately culminated in the "apotheosis" of my banjo career. In 1978, I managed to place second in the National Banjo Championships, which are held every year in Winfield, Kansas. And at that time, I was living in Boulder and playing in another band there. Bluegrass music, and the bluegrass music community, had become a big part of my life. I was a monthly columnist for Banjo Newsletter, which is the national banjo magazine. When I eventually moved out to Caltech in Pasadena, CA, I used to frequent a place called the Banjo Café in nearby Santa Monica, which featured live bluegrass performances every night, and which served as the cultural center for bluegrass in the Los Angeles area. At one point, I wrote a column for Banjo Newsletter praising the Café. One evening while I was having dinner there, a waitress came up to me to thank me for the column I’d written, and all the extra business that it had brought in. I asked her out on a date. Skip forward to today, and she's my wife of 35 years, Kathleen! So, I owe my loving wife to bluegrass music (laughs), and probably my sanity, as well, because when I'm not doing science, I have a great time playing music, alone or with others. I don't just play the five-string banjo. Back around 2000 or so, I switched to learning the mandolin, and I play a lot of mandolin these days. I attribute this love of music to my mother's side of the family. My father couldn’t even hold a tune, and he was always asking family members to turn off the damned music so that he could concentrate on his work.

Zierler:

Right, right. Where did oceanography and Chinese language and literature go?

Block:

Well, the oceanography all got washed out because, as I mentioned, you couldn't take oceanography courses until you were a sophomore at the University of Washington, so I never got to take any class in oceanography, and that never happened. But I still had, in the back of my mind, a passion for living organisms, and especially an appreciation for their complexity, and their diversity, along with a real interest in the physics of how living organisms manage to adapt to diverse environments, for example, whales and fishes. So, there was that. Chinese language was left behind, too, because I got frozen out further study by moving to Oxford, where I only “read” physics. Plus, I spent my first year at Oxford studying like crazy just to catch up with my British colleagues. But you only need to pass two exams to get an honors B.A. from Oxford. It's an interesting system. Or at least it was back then. But I think it's still that way. What would happen is that at the end of your three years there, you would take Finals. The final exams. They're very unlike American finals, which happen at the end of each quarter or semester for every course. Oxford Finals consisted of a three-hour exam in the morning, and then a three-hour exam in the afternoon, every day, for six days straight. They would test you on absolutely everything you'd learned over all three years there. And there was only one other set of exams that you also had to pass, and those were known as "Mods," which stood for Honours Moderations Exams. Incidentally, the results of both Mods and Finals for every student used to be published in the London Times. Mods were officially known as First Public Exam, while Finals were known as the Second Public Exam. Mods is a sieve exam: it’s designed as a filter to see if you should be allowed to continue at Oxford, or if you should fail out. At the end of the first year, we all had to take Mods, and actually, a couple of my fellow first-years failed it, and were “sent down,” as they say. The actual passing grade you get on Mods only matters if, when you finally take the Finals, you happen to get a borderline grade. In the event that you got a borderline grade, your Final grade would be “moderated” either up or down, depending on your Mods performance, from two years earlier! And that's why Mods are the Honours Moderations Exams. Other than that, you simply had to pass Mods in order to continue at Oxford. I actually went to something called a “college reading party” up in the UK’s Lake District, before the Mods exams, to study hard for these. For me, the Mods were the hardest set of exams I've ever had to take in my life. And not the Finals. The Mods. But luckily, I passed Mods and was allowed to stay at Oxford. But again, you only get to study one subject, and so I had to leave Chinese behind, and I had to leave oceanography behind. Still, I maintained some level of interest in these things.

In my final year at Oxford, for reasons that are even now not clear even to me, I took the Theory Option, though I'm not a theorist and I 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, okay, I did it, although it was probably a mistake, in retrospect. I suspect I did these things, at least partly, because many times in my life, people have doubted that I would be able to do something, and it was my way of saying, "In your face, I can do this!" So I took the theory option, which involved a lot of mathematical physics (which I have long since forgotten), and was mostly about things like quantum mechanics and particle physics. So, I looked around, and where were the physicists who did particle physics, back in those days? Well, they were working on ever bigger and bigger experiments. The particle experiments of my father's era involved perhaps a dozen people. And today, the physics collaborations at CERN on the LHC, for example, involve literally thousands of scientists. Even back when I was at Oxford, CERN experiments on the intersecting storage rings, the ISR, involved several hundred people. But I didn't want to become one name on a hundred-author paper. That was not my idea of science.

And the other thing that I knew, for sure, is that I didn't want to go through academic life being known as Marty Block's son. It was really important to me to be able to establish an independent identity. Up to that point, if I was in a physics setting and I went up to some established scientist, and we'd begin a conversation, we'd eventually get around to the point in the conversation where they'd ask me "Are you Marty Block's son?" And I'd have to concede, sheepishly, that was the case. So I looked around, and I decided that biophysics was potentially very interesting to me. Now, I'd never taken a single course in biophysics. I'd never read a single paper in biophysics. I really didn't know a thing about it, truth be told, but I thought perhaps, given my love of nature and organisms, and given my interests in the outdoors through skiing and other things, that I could somehow combine my interest in physics with my other interests. And not worry hear a thing about being Marty Block’s son. And so, out of the blue, during my last year at Oxford, I wrote off to a series of physicists who'd moved into biology. None of these people knew me from Adam, but the essence of my letter was this: "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 that I do? Maybe I could work for you?" That sort of thing. It was hopelessly naïve.

Zierler:

And Steven, I'm curious, what was your classical training in biology at this point? Were you entering into a brave new world?

Block:

I had none whatsoever. The only biology class I'd had was back in high school in Evanston, Illinois. I had one extraordinary biology teacher there who was African American, by the way: a Mr. Gillespie. In one extraordinary weekend, he decided to take a few students from his class and do something special. He had us isolate DNA from a calf thymus gland. Today, of course, you can do nearly the same thing with a few strawberries, a bit of alcohol, and some Ziploc bags, and it's a science exercise that little kids try in grade school. But back then, the biochemical recipe was quite a bit more complicated, it was a pretty unusual thing do to. We had to go to the butcher shop's to get the thymus glands, or sweetbreads, then meet at the professor's house for the weekend, where we worked on the prep for nearly two days. I think that experience sort of stuck in my mind. It became another one of those snitches of memory that stay with you, you know, 10, 15 years later, and you still remember that you had such a good experience doing it. But the truth be known, I had no biology background, no training, no experience, no real knowledge of modern biology, when I wrote off that letter from Oxford. I just knew that I wanted to do something related to physics and it had better not be particle physics.

Zierler:

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?

Block:

Well, I think the popular answer would likely be yes, but the true answer is no.

Zierler:

At the time. I mean, that's what I'm asking. At the time.

Block:

At the time. Of course today, I'm very interested in advancing human health, and if I could do anything that would really help with SARS-CoV-2, I would be actively involved in that. Back then, I was not -- if I'm being totally honest -- motivated by anything to do with human health. I didn't want to be a pre-med. I didn't want to become a doctor. In fact, I had cultivated a kind of healthy disdain for doctors. A disdain which has only been nurtured, by the way, over the years, by my experience. As a postdoc at Stanford, I actually helped teach a few classes in histology to the med students. I'm well-aware of what med students know and what they don't know. And most of them don't know. Doctors are strange beasts, and medicine is a strange profession. It’s certainly not a science. It turns out that the placebo effect is enormously important throughout medicine. In many trials that have been done, as many as a third, or even more, of the patients receiving a placebo will report some improvement in their medical condition. This not only holds true for medicines taken orally, but experiments have even been carried out with placebo surgery, that is, sham arthroscopic surgery on the knee. And many people reported improved outcomes even after getting fake surgery, simply because they believe that it should have helped. Doctors know all about this powerful psychological effect, and they’ve known about it for centuries.

One thing that's of vital importance in the medical world is a good bedside manner. What's important is that 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 thing. That you will become better as a result of his ministrations. When doctors are unconvincing, the chances are that you may not get better, even with the best medicines. Statistically speaking, that is. Looked at another way, doctors are in the professional business of lying to you. They're in the business of trying to make you feel better about yourself and any treatment plans they provide. They are often less than sanguine about the downsides. Instead, they tend to play what they know, or think they know. They will say things like, "I've seen this before, I've seen many people get better.” It’s all about a “don't worry about it, we'll get you through this" kind of attitude. My frank impression of that was very negative, especially when I was a student. It continues to this day, because I often know what doctors don't know, I know what the sorry state of medicine really is. Modern medicine is a more scientific discipline then ever, thankfully, but there's a huge side to medicine which hasn't advanced all that much in centuries. Some doctors will be frank about this and tell you that psychological side is terribly important, but something of a mystery. But I didn't want any part of that myself, because I thought it was so terribly unscientific. Also, it’s quite hard to address by any current methods. Even to this day, I'm a terrible patient with my own doctors, because I always want to know the unvarnished truth, delivered without condescension or qualification. With today's internet, of course, you can research everything up the wazoo. I'm certainly no hypochondriac, but on the other hand, I try to learn all that I can. Doctors are not especially prone to communicate in straightforward ways, I’d contend. The truth can often be depressing, and it can act contrary to the placebo effect.

I have a tempered respect for what doctors do, but I have never wanted to be one. I wanted to go into science. As to your question: I wanted to get into biophysics, and it had nothing whatsoever to do with any health aspects on the biomedical side. In fact, I didn't want to work on humans, at all. I was interested in finding out something fundamental about biology. So back to my story, which is, I wrote off all these cold letters, and unsurprisingly, I heard back from very few people. And the one or two I did hear back from were mainly negative. But I got one single letter that changed my life. That letter was from Max Delbrück. Max was a Nobel laureate. He was famous as one of the founders of modern molecular biology. You can read all about his contributions to biology in books like Horace Judson's “Eighth Day of Creation,” for example. Max had been a German physicist, and an early contributor to the Copenhagen school of quantum mechanics, led by Niels Bohr. He worked with Lise Meitner and others, and made some fundamental, early contributions to quantum mechanics. And famously, Max read Erwin Schrödinger's “What is Life?” book in the 1920’s. He eventually emigrated from Germany to the United States, first working at Vanderbilt University, and later at Caltech. He ultimately received the Nobel prize, but it was awarded, I’d argue, not so much for what he nominally got it for, which had to do with proving that mutations were random and unselected (i.e., not induced, supporting Darwin’s ideas about evolution, as opposed to Lamarcks’s; this was the Delbrück-Luria Fluctuation Test). Rather, in my opinion and the opinion of a good many others, he really got the Nobel prize for founding a school of thought. He surrounded himself with a number of like-minded scientists from many disciplines who were all trying to hunt for biophysical principles that could explain life. And those individuals included folks like a young Jim Watson, George Gamow, Seymour Benzer, Francois Jacob, Jacques Monod, Sidney Brenner, and others. They would all go on to make major contributions to molecular biology.

Max was a force of nature. He founded the famous Phage Course at Cold Spring Harbor Labs on Long Island, New York, held during the summers, and which, over the years, became the “glue” that held much of the nascent field of molecular biology together. Max introduced all sorts of scientists to microscopic life: teaching about phage (bacterial viruses), and also about viruses and bacteria in general. Spinning off this effort were numbers of individuals who later populated the whole field of molecular biology.

Max was growing towards the end of his career when I first contacted him in 1974. After he’d received the Nobel prize, he decided to switch to working on a different organism, called Phycomyces, which is a phototropic fungus. It's basically a kind of mold that makes giant, single cells, and these cells can be nearly as long as your finger, except that they're extremely narrow. Phycomyces exhibits a panoply of responses to the environment. It can respond to light, it can respond to gravity, it can respond to touch, it can respond to wind. It has a mysterious “avoidance response” that causes it to grow away from nearby walls, even in the dark, and without ever touching them. Max was interested in studying sensory transduction in this organism. Anyway, to make a long story a bit shorter -- and this is one long story! -- I got this letter back 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? You should come to Cold Spring Harbor." And so, I literally flew from Heathrow Airport to JFK in the summer of '74, took a shuttle van straight across Long Island to Cold Spring Harbor, and spent the summer of 1974 working for Max. It was a total immersion baptism in biology, in a fabulous, high energy place. The field of biology has the Marine Biological Labs at Woods Hole, MA, and it has Cold Spring Harbor Labs on Long Island, NY. Physics, for its part, has the École de Physique des Houches in Les Houches, France and it has the Aspen Center for Physics in Aspen, CO. So, I spent my first summer out of college 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 work on henceforth. So, I sought out Max and I asked him what I should do, going forward. That summer, I’d done some math to model how growing Phycomyces would bend in response to polarized, UV light, based on whatever the orientation of its photoreceptors might be (which is what we wanted to determine) and the light polarization direction: this involved using some vector calculus and a whole bunch of trigonometry (because I'd had taken the Theory Option, after all. What else was I going to do?). I was fascinated by all the experiments going on around me. Max said to me, "You know, what you really need to do is learn some biology, because you really don't know any." I’d had no real training in it whatsoever, in fact: my last biology course had been in high school. So Max said, "You know what you need to do? You need to come out to Caltech," which is where he worked. "Come to Caltech for a year, do some experiments, take some classes, and read Watson's book." By which Max meant the “Molecular Biology of the Gene” textbook, and not his pot-boiler, “The Double Helix.” (laughs) Although I eventually read them both. "And after that, you should apply 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’s that, Max?" And he said, "Well, I don't have any money to pay you." I explained to him, "Well, look, Max, I've got a little money in savings, and maybe my parents can help me out? I would love to come out and intern, basically, for a year." And he said, "Well, let me think about it." Max then did something truly extraordinary. As a famous Nobel laureate, Max had been invited to go to the University of Konstanz, in Germany, on the Bodensee, to deliver a series of lectures about his life and work. He'd originally turned them down, but he called them back to say that he would go after all, and he did this because he was slated to receive a rather large honorarium, which, in essence, he turned into the Steve Block fund. He got back to me two days later, saying, "Don't worry, I've raised the money. You should come out and work with my group at Caltech next year." So, I owe Max my career. I owe this man my livelihood. I owe this man a debt of gratitude that I'll never be able to repay.

Zierler:

Yeah. And when you say you worked with him, you really worked with him. Not his post docs?

Block:

I really worked with him, and he always had a small group, so we got to see a lot of him. I wasn't even a grad student at that point.

Zierler:

No, I'm saying you didn't work with his post docs. You really worked with him?

Block:

I worked under Max, but also directly with one of his post docs. Technically, I was hired as the dishwasher for the Delbrück lab. I washed and sterilized all the dishware and pipets, and this was before the modern era of disposable plasticware! I ran the autoclave. I made potato dextrose ager, which is the medium that you grow Phycomyces on. I poured medium into Petri plates and growth vials. But Max had a postdoc named Ed Lipson, who eventually became a professor at the University of Syracuse. Ed let me do some experiments on Phycomyces with him. Ed, along with an earlier student of Max’s, Ken Foster, had built a tracking microscope to follow the growth of Phycomyces in real time. You could stimulate the organism with blue light, but it couldn't see red light, so you could bounce some red laser light off of it and measure its position very accurately, and therefore its growth in response to blue light stimuli. I did all these experiments on phototropism and the light growth response under different directions and durations of light, studying how the organism can adapt to persistent levels of light, and manages only respond to changes in light about the ambient levels. By the end of the year, I had completed enough experimental work for a research paper, which eventually got published, along with Ed Lipson, who also taught me so much about error analysis and statistics. The other thing that I did that year was to apply to graduate schools. I took the GREs, and thanks to the physics training I'd received at Oxford, got a great score on the GRE in physics. I didn’t even try to take the one in biology. I applied to biophysics programs all over the country, and thanks to my scores, and almost certainly to Max's letter of recommendation, I got into just about everywhere, including Harvard, and especially including Caltech, where Max was. Because frankly, I just wanted to stay at Caltech.

Zierler:

Did he encourage you in any particular direction?

Block:

Well yes, that was the next thing that happened. So, I'm wandering around a bit, trying to figure out what to do next. Max sees me in the hallway -- and this was in the basement of a building at Caltech, where I was working on these experiments -- and says that he wants to have a word with me. So, we go to his office, and he sits me down. Max looks at me and he says, "Steeff--" He called me “Steeff,” in an aristocratic German accent that I can’t do proper justice. "Steeff, I want you to go to Colorado." I answered, "Why should I go to Colorado, Max?" Privately. I was disappointed that he hadn’t suggested that I stay at Caltech, and continue work with his group. And he says, "I want you to work for Howard Berg." So, as it turned out, and unbeknownst to me at the time, Max was on his last legs. He'd been diagnosed with a brain tumor. Sadly, he was to die within the next few years. But Max was really enamored of the work of Howard Berg, who was, at the time, at University of Colorado. Berg had also been trained as a physicist, working with Norm Ramsay on the hydrogen maser at Harvard, for which Ramsey received a Nobel Prize. Berg had gotten interested in biochemistry, and he was one of the people who actually invented, or co-invented, the ubiquitous SDS polyacrylamide gel that everyone uses to separate proteins. Berg had turned his interests to chemotaxis in E. coli, that is, to the motion of these bacteria towards chemicals that they liked, and away from chemicals that they didn't. Berg is an exceptional experimentalist, and to study chemotaxis, he, too, had built a tracking microscope. Except that Berg’s invention was in a league all its own: it was so small, sensitive, and fast that it could follow the motion of an individual, micron-scale bacterial cell as it swam, responding in mere fractions of a second. He had developed this one-of-a-kind instrument originally at Harvard, and then moved to the University of Colorado, shortly after the formation of a new department there, which is still going strong to this day. In fact, it just celebrated its 50^th anniversary: the Department of Molecular, Cellular, and Developmental Biology (MCDB). It was my honor to have been invited to their anniversary celebration, held recently, as one of their proud alumni. And, of course, I got to play my banjo at the festivities.

Zierler:

Now you mentioned you had a sister, was she still in Boulder?

Block:

No, she'd long since graduated and moved away and was living elsewhere, so I had no relatives living there, although my parents were spending, at that point, all their summers in Colorado, but out in Aspen, which is on the other side of the Great Divide, which was a good three and a half hour trip from Boulder. But Max had, in essence, set up an arranged marriage for me. He was a big fan of Howard Berg's.

There's a famous quotation from Max, which I probably should relate. This requires yet another bit of a digression. By the early 1970’s, Max has spent almost 25 years studying this phototropic mold, Phycomyces, which turned out to be something of a mess, as a model research organism. It has multiple nuclei, not just one (it’s a “syncytium). It's extremely difficult to work with genetically. It does have a sexual cycle, but it takes months to go through it, and the long generation times make for slow progress. From a genetic standpoint, it was a nightmare. Biophysically, it has many complicated sensory responses, but few identified sensory receptors. To this day, we still don't know how most of its senses work. In hindsight, it was a poor choice for research. 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, work from the pioneering bacteriologists W.F. Pfeffer and T.W. Engelmann. Adler re-discovered the fact that E. coli, the darling organism of most molecular biologists, itself exhibited a large number of sensory responses, including thermotaxis, aerotaxis, and chemotaxis. Why had nobody been working on this already? Well, it turns out that the dominant strain of E. coli that was being studied in molecular biology laboratories all over the world, had been grown for so many generations in labs on rich media that it had lost all its flagella. It couldn't swim – because it didn’t need to. Evolution will do that. So, nobody had noticed any sensory responses, because their bacteria were immotile. So Julius Adler took a field trip to the sewage treatment plant in Madison, Wisconsin, and re-isolated native E. coli, get a truly wildtype strain. He named this strain AW405, which stood for Adler Wisconsin 405, and it became the parent strain for working on bacterial swimming and sensory responses. Howard Berg spent some time visiting Adler, got excited, started to dedicate his career to understanding bacterial motility and chemotaxis. To this day, Berg has published some of the very best papers on E. coli chemotaxis and the function of flagellar motion. Berg was the scientist who proved that bacterial flagella literally rotate, like the prop on a submarine, because they're each driven by a rotary motor from the base. These motors, in turn, are powered by an electric current generated by metabolism in the cell, known as the protonmotive force. Protons pass into the cell, through the motor, driving it into rotation. I did some of my graduate work on that amazing motor.

But back to our story. Someone once asked Delbrück, if he was so interested in sensory transduction, and since he was already famous for picking useful model organisms (like bacteriophage and E. coli), then why hadn’t he just stuck with E. coli, which he’d been working with all along, to study sensory transduction? That is, why did he switch organisms to Phycomyces, which turned out to be something of a dead end, and not stay with E. coli? Reportedly his answer was, "Because I didn't know how to tame them.” (E. coli, that is). I have always found that answer to be inscrutable.

Zierler:

How does one tame E. coli?

Block:

Anyway, if anyone could tame them, it was Howard Berg, and he was the person, as I said, who’d built this amazing tracking microscope. So, after Max told me to go to Colorado, I tore up my acceptances to Harvard and Caltech and other places. I moved to Boulder, only to discover that everyone else in the incoming graduate year was scheduled to doing rotations through different labs. But not me! It was understood that I’d be working for Howard Berg. There was, in essence, an invisible nameplate on a desk in his lab with my name on it. So, I began working with Howard Berg. This was also ironic, because Max subsequently passed away, just a few years later. Caltech, naturally, was looking for a biophysicist to replace him, and who did they recruit but Howard Berg from the University of Colorado? So, I was something of a human yo-yo. I spent my first year out of college at Caltech with Delbrück, but I also finished my Ph.D. at Caltech with Berg, working in a laboratory close to where Max had been. Max was the first formative influence in my scientific career, and Howard was the next. Although I was excited to be at Colorado, and very interested in the system of bacteria and chemotaxis, I was also somewhat lazy and easily diverted.

In Boulder, there's a vibrant community of folk, oldtime, and bluegrass musicians, which I enthusiastically joined. For the first few years, I would spend my summers traveling around the country in a Volkswagen camper bus (christened “Ludwig Van”), playing in bluegrass festivals, entering banjo contests, winning a few of them. If I won enough money, it paid for the gas to travel to the next festival. But I was supposed to be back in Boulder in graduate school, doing research. But Howard Berg, for reasons I don't fully understand (but am nevertheless appreciative of) tolerated this behavior. It was behavior, hypocritically, that I probably wouldn’t have tolerated in my own graduate students. But Howard allowed me to pursue my passions during large parts of the summer, and even in the winter, occasionally, when I would take off to go skiing and return a day, or three later. Back in those days, if you bought it early, you could purchase a season ski pass to Lake Eldora, which is the local ski area, for around $25. And you could take a bus there from the Boulder Library, up Boulder Canyon, to go night skiing. So, I would sometimes work until three or four in the afternoon, grab my skis and boots, hustle down to the bus station, and head up to Eldora for night skiing. I would ski until closing, around 9:00PM, return to my apartment, collapse in a lump, and drag myself into the lab in the late the next morning. This went on for a some time.

I was in a bluegrass band, too, and the band got pretty popular, playing the local bars on weekends. We also played downtown, on the mall. I got better on the banjo, and I won that contest I told you about earlier. Then, Howard went off to Paris, France, to spend a year on sabbatical. Before leaving, he sent me a frank note, which I no longer have. In retrospect, I should have saved it and framed it. His text was short and to the point, to the effect that, "Well, Steve, you're bright and all. You have the potential to do some great work. But unless you manage to buckle down and get more done, you're never going to amount to much in science." His message was all-too true, and it shook me to my core. After that, I underwent a kind of phase change in my behavior, and that change was abetted by the fact that Berg left Boulder the next year to accept a position at Caltech. I moved with him and the lab back to Caltech. This would have been in January of 1980. Unlike CU in Boulder, which was a lotus land of infinite distraction to me, Caltech in Pasadena was more like a priory. You could enter the lab building at 10:30PM and most of the lights would still be on, with plenty of grad students still working there. It was a totally different environment from Boulder. But I went with it, spurred in part by Howard Berg's admonition.

Zierler:

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?

Block:

Oh, absolutely, and in fact, my doctorate from Caltech is actually on the biology side. So, I technically have a doctorate in biophysics. At Colorado, I was required to take a lot of courses in biology. I got really deep into molecular biology, and the intersection of physics and biology. So much so, in fact, that the graduate students in my year even created our own course, called Bioenergetics, about how organisms process physical and chemical forms of energy. It was such a success that it was taught in Boulder for several years after I left. So not only did I take classes, I wound up teaching classes, and this really helped me to develop my communication skills. Also, believe it or not, I took my Ph.D. qualifying exams in biology not once, but twice. While I was still at the University of Colorado, but soon to leave with Howard Berg for Caltech, they told me, well you're leaving without a PhD. But you’ve taken all the required classes, and you could get take a Master’s degree, although that would require passing the Ph.D. qualifier, as well. So I sat those exams. Back in those days, you also had to take a foreign language exam: this was a requirement for the Ph.D. I took it in French (without studying) because I was pretty fluent in French, thanks to my schooldays in Geneva. I passed the written test and the oral parts of the quals, too. They had both. When I got to Caltech, I thought I’d automatically get transferred into their doctoral program as a qualified candidate, but they were unwilling to allow that, even though I was Berg's student, and had only just passed the quals in Colorado. So, I had to pass the quals in biology at Caltech, too. By the time I became a postdoc at Stanford, I was pretty well trained in biology, and arguably knew as much, or more, as the next person in the lab.

Zierler:

And in terms of the day-to-day, where you using physics or was this really, truly immersed in a biological world?

Block:

It was truly immersed in a biological world. I think it's fair to say, even to this day, that it's probably easier to teach some biology to a physicist than it is to teach some physics to a biologist.

Zierler:

Right. I've heard that. Yes, yes.

Block:

And the difference. Well, there's a kind of difference in the field itself, which I might describe in the following way. Physics is, in some sense, a “vertical” field. The best theorists can very often derive (or at least estimate) everything that they need from a few simple assumptions and a knowledge of some basic equations and physical properties. It's not quite that simple, of course, but back-of-the-envelope physics 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 he even taught a famous course at Harvard with exactly that name. It's possible in physics – a goal, in fact -- to develop a fairly simple understanding of things, and then make it more complex from there. And you can do this with a working knowledge of basic physics and not a whole lot else, except native smarts. The best experimental physicists also have some knowledge of material properties, measurement techniques, and they can build directly upon things they already know. So even experimental physics is somewhat of a vertical field. I would describe biology as more of a horizontal field. There's a huge amount of information to assimilate, and the best biologists are often able to bring rather disparate bits of information to the bear on a problem, and gain new insights in that way. So, the best biologists are, in some ways, a bit more like Jeopardy champions on TV. They have at their command a huge knowledge of facts, and also about inter-relationships across fields and subjects. The kinds of skill sets required rather different. But if you can pick up things quickly and remember things, you can be a biologist. And biophysics, of course, is an attempt to take the tools, the strengths, the precepts, and -- most importantly -- the mindset of physics, and apply it to biology.

Zierler:

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?

Block:

The other direction can certainly happen, in principle. That said, it's comparatively rare that a biologist has made a contribution to physics in the modern era, whereas quite a number of physicists have contributed in important ways to biology. Max Delbrück and Howard Berg, who were my mentors, are certainly among them.

Zierler:

Is that simply because physics is more fundamental? It lends itself in that direction?

Block:

Well, you know, physics is often called the mother of all sciences. And here's an interesting sidebar, which relates to how degrees get awarded during the graduation ceremony at Oxford University, when I went. The degrees in different subjects get awarded in a strict order, namely, in the sequence with which the associated schools joined the university, historically. The first degree awarded is always theology, since the institution started as a religious school. Then came English, because rhetoric was one of the earliest subjects. And philosophy also came early. But the fourth or fifth degree awarded -- I can't remember which anymore -- was in physics. You might wonder why. Well, physics wasn't always called physics. It used to be called “experimental philosophy.” That’s a great name for it, which gets to the very heart of how we think about science.

Zierler:

(laughs) Right.

Block:

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 universe around us to try to understand how that universe works. There can be no more fundamental, and no more noble, thing than the pursuit of information. 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 same thinking can apply to biology as well. Incidentally, biology, in case you didn't know this, is also a comparatively new word, and considerably newer than physics. If you read Darwin's Origin of Species, for example, the word biology doesn't appear anywhere in its pages! In fact, it was popularized later by the Germans, and it entered the English lexicon relatively late. Physics, by the way, is not such a great word when you think about it. It's certainly not as noble-sounding as experimental philosophy.

But let’s get back to the story, and what we were saying. The physics that I do has been always characterized by trying to understand, in a more fundamental way, how something in Nature works. And much of my career has been spent trying to understand how Nature’s molecular motors work. Virtually all organisms have molecular motors, from tiny bacteria up to giant blue whales. Your muscles contract, and your brains think, and all these things happen as a direct result of proteins that have evolved to the point where they can produce movement. Insofar as there's a common thread working through my career, it started in sensory transduction first in Phycomyces. I then transitioned to working on sensory transduction in E. coli, to understand their chemotactic behavior, and that drew me to their flagellar motors, because chemotaxis is achieved by driving their motors either clockwise or counterclockwise, depending on the chemicals they're sensing, in a probabilistic fashion. So that got me interested in motor directional switching, and later, as a postdoc, in torque generation by the motors. I then moved into studying myosin motors, which are the motors responsible for muscle contraction (among other things), as a postdoc at Stanford. Eventually, I got into kinesin motors, when I started working independently as a scientist. And then, from there, back to the fundamental enzymes of life, including RNA polymerase, which is the enzyme that reads the genetic code. This polymerase is also a motor, if you think about it: one that moves processively along DNA, transcribing a corresponding RNA as it goes. But serving as a motor is an integral part of its function.

In a way, most of my scientific career has been spent looking at the production of motion in Nature, which, of course, requires energy. How is the conversion of chemical energy into physical motion carried out at the molecular level? This is the perfect job, in my view, for a biophysicist, because it combines trying to understand aspects of the physics of the motion, and trying to understand how energy is transduced in order to make life happen. And trying to understand how such motors interact with cofactors in purposeful ways, and how they're regulated in cells and so forth, and so on. Larger organisms are built out of smaller components, and I think there's a growing appreciation for the sophistication of those small components. Particularly, as I say, since I got my start with one of the founders of the modern field of molecular biology. Molecular biology really got its start when DNA was first discovered, and eventually its 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 emerged, 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. Today, a lot of work in biology is concentrated not at the organismic level and ecological level, and not so much with the folks with the pith helmets and butterfly nets, but rather with scientists, often with physics training, who are working at the level of single molecules.

Zierler:

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?

Block:

To this day, biomedical science has not been much of a motivating factor for me. I suppose I'm being 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, and how those simple parts interact. One thing we've gained an appreciation for is that proteins are nanoscale machines. They do nano biology much better than any human has ever done nanotechnology. They’re atomic-scale accurate; they're reproducible. I have the deepest appreciation for these machines and how they work. In many ways, I've dedicated my scientific career to trying to understand better how all that works. This is a fundamental question, and if it happens to have immediate or even indirect applications to human health, then I'm all for that, wonderful, mazel tov, go for it.

Zierler:

But that's not what got you into it in the first place.

Block:

But that's not why we do it, exactly.

Zierler:

Yeah, right.

Block:

I am at once reminded of Feynman's famous quote about physics, which is that physics is like sex. Sure, it has some useful outcomes, but that's not why we do it. (both laugh)

Zierler:

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. (both laugh)

Block:

Well, I may have garbled it a bit, but that was the sense of the quote. The fact of the matter is that I'm interested in biology for what it can teach us about the world around us. Why do particle physicists study particles? I think they're interested in what is truly fundamental in this universe. In the 1950’s it was particle physics, and then it was quarks and quantum chromodynamics, and today it's string theory and other attempts to try to understand at a truly fundamental level what matter is, and what are the forces that engage matter. And of course, they’re also active on the cosmological scale. Physicists are interested in all scales of complexity, but the most exquisite example of complexity that we have are living organisms, including ourselves. The fact that we can even understand ourselves is almost incomprehensible itself, and my interest is to try to de-mythologize at least part that, and to try to understand better at a fairly low level of complexity, but one which is well up from particles and atoms, and well up from simple molecules, but the level of biological macromolecules, which have hundreds of thousands of degrees of freedom, and are in fact quite complex in their own right -- how do these molecules interact and produce sophisticated types of behavior? I would especially include here, the case of molecular motors, and the production of displacement and force, for motion. How does this happen? 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 protonmotive of force, driven by flux of protons, and that includes the bacterial motor that we talked about. It also includes the device that makes most of the ATP in our bodies, the ATPase (ATP synthase), which is responsible for fueling most of our energy usage. Once the ATPase has done its job, we have lots of ATP, and that ATP is then, in turn, used to run other classes of motors like myosin, which makes your muscles contract, and allows kinesin motors to move, which ferry cargo in your nerves and brain and other places, and which pull the chromosomes apart in mitosis. All these motors use ATP. It's probably fair to say that the molecular mechanism by which any of them works is not yet fully understood. It's being worked out in our lifetimes.

Zierler:

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?

Block:

The research I'd done at the end of my career at Caltech was, in many ways, responsible for everything that was to follow. This was with Howard Berg, who as I said, right after my time with Max Delbrück, had this incredible effect on my life. I owe the start of my career to Max Delbrück, and I owe the meat of my career to Howard Berg. Howard Berg was interested in the flagellar motor. One thing you can do with a bacterium is what's called “tether” it. You can take a bacterium and break off most of its flagella. These filaments are somewhat brittle, so you can easily do this using hydrodynamic forces, shearing them off with rapid flow. You then take a bacterium with this stubble, that is, with a little piece of one flagellum that's sticking out from the cell, and attach it to a piece of glass. You can do this using an antibody against the flagellar protein, but there are also other ways of doing it as well. So now, one end of the flagellum is stuck to the glass, and when the bacterium tries to turn its motor, the tail wags the dog, and the body of the cell goes round and round and round in circles. You can see this rotation easily under a light microscope. Now, the bacterial motor has a gear shift, so the motor will drive the cell clockwise for a time: about one second, on average. Then, it will switch gears and drive the cell around counterclockwise for a time. This clockwise versus counterclockwise behavior gets purposely modulated and ultimately, it turns out, that’s how a bacterial cell is able to move up gradients of chemicals. It runs, and then it tumbles, and runs and tumbles. The runs turns out correspond to periods of counterclockwise flagellar rotation, and tumbles turn out to correspond to the periods of clockwise rotation.

All this was all worked out by Berg and others in the 1970’s. The details of how that works are another topic altogether. But bacteria have this gear shift, and they have this motor, and that's absolutely fantastic to my mind. It turns out the motor is made of about 20 or 30 different components, that is, different types of proteins. It's about the size of a small virus. So, it's a very complicated thing compared to most other molecular motors. You can take tethered cells and watch them go around, and monitor bacterial behavior conveniently in place. A tracking microscope, of the type first built by Berg, is no longer required. If you take a cell that is missing one of two specific genes -- these genes are called “mot” genes, M-O-T, for “motility”. There are two alleles, motA and motB, so there are two flavors of the mot gene. If you're missing one or both Mot proteins, the bacterium can still make motors. It can still make flagella. You can tether the cells, but they don't turn. An experiment that I did at the end of my graduate career, in combination with colleagues, was to place one of the mot genes back into a mot mutant where the gene was otherwise missing. The mot gene we introduced was under the control of a plasmid, which is a small piece of genetic material that is independent of the chromosome. That plasma could be switched off, so it's not expressing Mot protein. You tether your cell, and of course, the cell's not going to turn because it doesn't have Mot protein. Now, you switch on the mot gene coded by the plasmid, and the cells, after a period of anywhere from 5 to 30 minutes, start synthesizing the Mot protein. When you look at a tethered cell, all of a sudden, after around 20 minutes of basically doing nothing, it abruptly starts turning, but slowly. Round and round and round. You keep watching it, and suddenly, boom, almost instantaneously, the rotational speed of the cell doubles, and now it's going around twice as fast. You watch it some more. Then, the speed trebles, relative to its first level. Then it quadruples. Then quintuples. And this goes on and on until it’s, roughly speaking, going about eight times faster: actually, somewhere between eight and ten times faster than when you started. So, what you see are steps in the angular velocity. The interpretation of this experiment is that the Mot proteins function, if you will, as the pistons of the rotary motor. When you have one piston incorporated, you have one-banger, and you can turn, albeit slowly, producing a small amount of torque. When you add the second piston, you produce twice as much torque, and since these cells are at such low Reynolds number, a physical regime where fluid viscosity dominates everything, whenever 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 are eight equal increments of torque. This experiment shows that there are at least eight force generators that drive the motor, and they’re all independent, because when you added the fifth one, you saw the same increment in angular velocity as when you added the first one. They function independently, each generating a fixed amount of torque that you can measure.

You can learn a lot about the motor in such experiments. That got me terribly excited about molecular motors in general. It got me so excited, that right around the time that we were publishing this work, another paper came out, from Jim Spudich, who is a professor at Stanford University, in the Medical School, and he and colleagues had worked out a clever assay that involved taking myosin, which is the protein responsible for muscle contraction, and sticking it onto the surface of little beads, then watching the myosin motors drag those little beads along the filaments of actin. Actin is found inside your muscles, and it forms the polymer track that myosin moves along, but the actin in muscle is harder to work with. Jim and his colleagues discovered that there's this plant: it's a common aquarium plant, called Nitella. It makes long, cylindrical cells that are big enough that you can actually cut them open. The Nitella cell is basically a cylinder, so you can cut it open lengthwise using a very tiny pair of scissors, of the type used in eye surgery, and lay it out like a flat sheet, which would expose the actin filaments, which stay attached to the cell wall. So, if you flowed in some of these little beads, which had myosin attached to their surfaces, and they reached the actin filaments, then all of a sudden, they would engage, and take off. You'd know this, because the bead, which you can watch in a low-power microscope, would start moving. This, even though you couldn't actually see the myosin and you couldn't see the actin, because they're at the molecular level. This was the first so-called in vitro motility assay for myosin movement.

Well, I'd been working on an in vitro motility system for bacterial motors. And I thought this was fantastic. I wanted to understand how myosin works, and someone had finally developed an assay for watching it work. By the way, Jim Spudich was later to win the Lasker Award for his part in this and further developments. So, I applied for a postdoc at Stanford to work with Jim, and I joined him there in 1984. At Stanford, I did some work trying to better understand the molecular mechanism of myosin. There was a theory, at the time, for how myosin might work. Actually, there were several competing theories, and this was just one of them. It was from a biochemist at Johns Hopkins named James Harrington. It basically went as follows. There was a part of the myosin molecule called the S2 region. The name isn't important. But the S2 protein region, Harrington had discovered by biochemistry, could transition from being an alpha helix, which is a long, extended helical region of protein, into a random coil. Now, a random coil has its ends closer together, on average, than an extended helix. Harrington had argued that by cyclically transitioning between an extended helix and a shorter coil, back and forth and back and forth, the associated motion could drive myosin forward in steps. This was the so-called “helix-coil transition” model of myosin motion, driven by the S2 region of myosin. So that was very interesting to me, because it also turned out to be a testable theory. It was testable because we knew how to chop myosin up into certain pieces using certain digestive enzymes. And, it turns out, you can make something called “light heavy meromyosin.” It's a confusing name, but all it means is a myosin molecule with the S2 region digested away from it, along with the rest of the myosin tail. The question was, would that residual part of myosin still work? We knew that it still had the ability to hydrolyze ATP, and that it still retained the bulky head of the protein, which was where we thought the motor really was. It still had all that, but it was missing the S2 region. Could we attach this reduced protein to little beads, and still get those to move in the assay? Well, the answer to that question was yes: they would still move. That immediately told us, at a stroke, that the Harrington model couldn’t possibly be right. Insofar as the S2 region did anything, it was not directly involved in the motility of the protein, because myosin can move even without its S2 region attached.

So that was that, and it was around that time that I started thinking that it might be possible to start to work on motor proteins at the level of single molecules. We were getting pretty close already, because in these myosin assays had multiple myosins, on the order of hundreds, attached to a bead moving on an actin filament. But maybe you could just dilute things down and down until you go to the point where your bead only had, say, only one myosin on it moving on an actin filament? At that point, you'd be looking at the output of a single protein. And then, wouldn't it be cool if you could actually measure the force associated with a single myosin moving? And measure the power stroke, that is, the step size? That is, monitor to see if it moved in discrete displacements, or somehow moved more continuously, or erratically. And when it moved, what force did it generate? How fast could it go? And especially, could you measure the so-called force-velocity relationship? That is, after all, what you do to characterize the performance of different motors. In your car, you know, you can measure the horsepower as a function of RPM, for example. You put your car on a dynamometer, and you measure how good the motor is by looking at its torque-speed relationship. So, for linear motor like myosin, that would correspond to measuring its linear velocity versus the force it generated. I’d wanted to do that, but at the time, the assays just weren’t up to it. You could try to titrate, using the fancy word, the myosin concentration down and down, but the assay simply stopped working before you got to the level of single molecules. Part of the reason for that, it turned out, is that myosin has what's called a short “duty cycle:” it engages the actin filament quickly and then immediately releases it. But once it releases, the actin filament-attached bead would simply diffuse away when you just had one myosin molecule on it. What you really require for the assay is a bunch of myosins, all on one bead. In that case, statistically speaking at any given time, one of them will remain attached. That way, a myosin bead that contacted the actin filament will just keep walking. Perhaps 20 or so myosins are involved in the motion, and they're dragging each other along like the itsy-bitsy spider. At least one leg is always in contact.

So, muscle myosin was not going to be great for a true, single-molecule assay. But right around that time, in 1984, a new protein was discovered at the Marine Biological Labs in Woods Hole, by Ron Vale, Mike Sheetz, Bruce Schnapp, and Tom Reese. That protein was named kinesin. Kinesin was also a molecular motor, and a little bit like myosin, but much, much smaller. In fact, to this day, I think it's still the smallest known ATP-based motor. Myosin hydrolyzes ATP, and kinesin does too. But kinesin has a different duty cycle. It tends to stay attached, so that the working heads of the protein don't tend to release from the filament. Now, myosin walks on actin, but kinesin walks on microtubules. It had 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 measure a single kinesin walking along a microtubule. If you could attach the kinesin molecule to a bead, much as had been done for the myosin molecules, and if you could apply a small force to that bead, then maybe you could see single molecules stepping, for example, or measure the forces that they generate, and even measure their force-velocity relationships? And so on.

So, that was the idea. I was even interested in trying to do it with myosin at the time, but people didn't know how to produce the kinds of minuscule forces needed to stop these tiny molecules. One of the ways of doing that, I thought, might be to attach a magnetic sphere to the bead, and pull on it using a magnetic field gradient. I’d done some back-of-the envelope calculations. We didn't know, at the time, the exact force levels that motor proteins produced, but we sort of knew what order of magnitude they were going to be. I’d computed that we needed some really strong magnets. You know, maybe getting up to a Tesla or thereabouts. At one point, I actually went to chat with some of the physicists at SLAC who had helped develop the wiggler magnets for the free-electron laser there, and I was talking to them about how we might produce magnetic fields and field gradients sufficiently large to produce these kinds of forces in a microscope. 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 so easy to integrate into a microscope, or I could do it, perhaps, with a permanent magnet. At the time, you know, the first really good permanent magnets were being developed which had neodymium, iron, boron, and so forth. So, I was working out some designs to try to adjust the strength of the magnetic field by having two magnets in concentric cylinders, and rotating them relative to each other, to null out the field in one configuration and have it be full strength in the other. But right around that time, I was also finishing up my postdoc, and it looked like this plan just wasn't going to be feasible. And it was just around that time that kinesin was discovered. So when came--

Zierler:

Who discovered kinesin?

Block:

Pardon?

Zierler:

Who discovered kinesin? Where did that happen?

Block:

Kinesin was discovered by Ronald Vale, Mike Sheetz, Bruce Schnapp, and Tom Reese at Woods Hole in the summer, working with a system that had been pioneered by some other folks at Wood Hole. Kinesin a protein that's abundant in all neurons, and it was first isolated from the squid giant axon. Research at Woods Hole is famous for studies of the squid, and a lot of early neuroscience was carried out with squid giant axons, including the Nobel Prize-winning work of Hodgkin and Huxley. So that was a specialty there. And there was also a guy named Bob Allen who was a well-known microscopist there, who was involved in the early days in trying to track down cellular motors, and who had developed ways to visualize components of the squid axoplasm (that is, the cell contents) using video-enhanced light microscopy, at the dawn of the digital imaging era. There's a complicated and controversial history about the discovery of kinesin, and who deserves credit for it, which is worthy of an entire book. Bob Allen, unfortunately, died of cancer, but he went to his grave angry about the way in which kinesin had been discovered without any credit going to him, not even partial credit. But it was Ron Vale, more than anybody else, who went on to purify the protein and successfully clone the kinesin gene after the motor had been discovered, and he has been a leading researcher over the years in many subsequent kinesin studies. But I wanted to concentrate on the biophysics of kinesin, and not on its genetics or the biochemistry.

Zierler:

And why did you recognize that kinesin was automatically a big deal for you in your research?

Block:

Two things. One thing is that a motility assay existed for kinesin, where it could move little beads, because that's, in fact, inadvertently the way it was first discovered, when it spontaneously attached to, and then moved, some beads that had been added to fresh squid axoplasm on a microscope slide. And the second thing was that it had this high duty cycle, which I was mentioning before, tending to remain attached to the microtubule. Myosin was a poor candidate, by contrast, and especially skeletal muscle myosin -- the one that we have in our muscles. This was a poor candidate because its duty cycle was so low, so you could only watch multiple motors work on actin, in concert. You couldn't get single motors to work. By the way, as a historical sidelight, since that time, different myosins have been discovered in the myosin family of proteins that are processive, and which do, in fact, have a high duty cycle. So you can now do much the same kinds of experiments with them, today, as you can with kinesin. But those are not muscle myosins, they are myosins that are found in other contexts in organisms. At the time, and this was 1985, kinesin was unique in that it moved slowly enough that you might be able to work with it, and it also looked like it might work at the single-molecule level, owing to its high duty cycle. Back then, I was finishing up my postdoc, and I had two options. One was to take an assistant professorship at Stanford in the Medical School, which I’d been offered, and the other was to rejoin Howard Berg, my former advisor, who had moved by that time back from Caltech back to Harvard. And Howard had also accepted a position at the Rowland Institute for Science. This was an amazing place, founded by Edwin Land of Polaroid fame. Land held more patents than any human in history short of Thomas Edison, and he was a one-man R&D department for the Polaroid corporation for many years. Land first worked on polarizing plastics films, and later, famously, on instant photography. When he retired, 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 over the river on the Longfellow Bridge.

Zierler:

And it was an independent institute? It wasn't connected with a school?

Block:

It wasn't connected with anything. It was built purely for Land's own interest and amusement. His family was, reportedly, not so thrilled about this, because his children, two daughters, had grown up scarcely ever seeing their father, because he was always off doing science, and they’d hoped that, once he retired from Polaroid, they’d be able to see more of him. But no, he established this private institute. People asked him where the name Rowland came from, and his usual answer was, "I'm not going to tell you." It’s thought that partly, it was a tip of the hat to Henry Rowland, who was the famous optics professor at Johns Hopkins, and who had produced the best diffraction gratings. Rowland invented a ruling engine, which made it possible to make very evenly-spaced, reflective gratings with nanometer-scale accuracy. These gratings could spread out the spectrum and allow you to do spectroscopy in a new way, especially for astronomy and looking at the constituents of stars. It was also possible that the name Rowland was a play on the name "Land" itself, his own name. Or perhaps related to the activity of his son-in-law, of whom he was enamored, had been quite a rower at Harvard. All these theories would still seem to be in play, because Land went to his grave without explaining the name. What he had in mind, I think, was establishing a kind of Noah's Ark of science on the banks of the Charles. It was a private playground where he could explore anything that he wanted. 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. For doing science research, he employed two of everything. He had two resident chemists, two physicists, two biologists. His idea was, apparently, that he would allow the scientists who worked for him to do whatever they wanted, too. They had an apparently unlimited budget to work on whatever they chose, at least most of the time. But if he needed their help with anything for a few weeks a year, say, they were expected to drop everything and help him on whatever his pet project was. Then, they could go back to doing what they wanted. My understanding was that Howard Berg had been recruited to the Rowland Institute with the understanding that when Land died or retired, Berg would likely become the next director of the Rowland Institute, after Land himself. So, Howard called me up and asked me if I would become his “co-conspirator,” and I use his word here. And I agreed, turning down the assistant professorship at Stanford. It sounded to me like science 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 explore anything I wanted in a new lab, with whatever budget I needed, as long as it interested me. I would have an opportunity to interact directly with one of the most creative minds of the century, in the form of Edwin Land, although at that point he was, I must say, getting on and in rather poor health. Anyway, I re-joined Howard Berg at the Rowland Institute.

Zierler:

And Steven, was your sense that this was a place where you could collaborate with academic colleagues? This was not necessarily a research island?

Block:

Well, it was a bit of a research island. Of course, the beauty of being in Boston (laughs)--

Zierler:

Right, sure.

Block:

--was that Boston itself is hardly a research island, so even if you're situated in a relatively isolated place within the city, you’re just ten minutes from Harvard, five minutes from MIT, and right across the river from Massachusetts General Hospital. And I had collaborations going on in all three places, at one point. So, from my perspective, it was lonely there on a day-to-day basis, because the building was seriously under-populated. It was a gorgeous building, with an enormous indoor atrium with bamboo growing in a garden and skylights, and a greenhouse, and a grand spiral staircase, and more. It also had some private apartments which were never open to us, but Land imagined that he might house some visiting scientists, and he'd put them up in luxury in these beautiful apartments, which had refrigerators and kitchens and lavish bedrooms, and bathrooms with jacuzzi tubs. These were all a part of the Rowland Institute at the time. Land's own private office had this enormous “Moonrise in New Mexico” photograph by Ansel Adams mounted above a big fireplace, then worth tens of thousands of dollars. Today, perhaps it’s worth hundreds of thousands of dollars. He had a spectacular porch with a view across the Charles river of downtown Boston and Beacon Hill. So, this was quite the place. But it was under-populated, so it was both an island of isolation, and not, all at the same time.

So, I got there in 1987. As I was moving across the country, I had a predecessor of today's laptop computers, something called the NEC Multispeed. It had two 720KB floppy disks, one of which was used to boot it up. And it had just a 12-line LCD display, which was alphanumeric. No graphics at all. I spent the time while my wife was driving, and when I wasn't, debugging software, with the computer plugged into the car’s cigarette lighter socket. Bill Press had written a first draft of his now-famous book, Numerical Recipes, specifically for the C language, called (of course) Numerical Recipes in C. He had given me an advance copy of the manuscript to see if I could find any mistakes in the code. I had a C language interpreter that ran on this thing, and I was running all of Bill’s routines through the interpreter, trying to find any bugs or quirks in them. So, when we got to Boston, I went straight to see Bill Press, with a list of about 10 or 12 things that were eventually corrected in the first edition of Numerical Recipes in C. I should mention that I'm acknowledged in two or three textbooks, at least in their early editions. In some ways, I'm more proud of those acknowledgements than any of my own papers that I’ve written. I was acknowledged in Lubert Stryer’s Biochemistry, which is one of the best, and best-selling, biochemistry texts of all time. I was acknowledged in an early version of Numerical Recipes in C. And I was acknowledged in another famous Harvard textbook, The Art of Electronics, by Paul Horowitz and Winfield Hill. So that was great: I managed to have useful input in all these different directions.

Anyway, the Rowland Institute was a fascinating place, and the fact that I had a carte blanche to do anything that I wanted was just amazing. Soon after I traveling across the country from California, and literally within a few days of being at the Rowland Institute, a very famous paper came out in Nature by Art Ashkin, who got the Nobel prize in 2018 for the invention of the laser-based optical trap, or optical tweezers. And I think it may have been Howard Berg who first drew my attention to the paper, in fact. It was in this paper where Ashkin reported that by using the right wavelength of light, you could actually capture individual bacteria and move them around under control of the optics, all without damaging them. I thought this was the greatest thing ever. But the fact that he could arrest live E. coli, which kept swimming afterwards, was of particular interest to me, because I knew the range of forces produced by swimming of bacteria, which I'd worked out many years earlier, as a grad student. And I realized right away that we were talking about piconewton-scale forces. But piconewton-scale forces were precisely the kinds of forces that I wanted to apply to 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 motor, then I needed to exert something on order of ten piconewtons. Of course, the exact number was not known at the time to anyone. But you know, fireworks -- not just light bulbs -- went off in my head when I read Ashkin’s paper. I thought it was just astonishing. I'd only just arrived at the Rowland Institute, but practically the first thing that I did was to start looking into buying a solid-state laser that would produce enough power to form an optical trap (Ashkin had used a conventional, lamp-driven laser, instead, which was huge and bulky). These compact solid-state lasers were only just reaching the market then, and the available power levels were still pretty low.

The next thing I started to do was to design how my own optical trap would work. And the only thing I had to go by was this God-awful diagram that Ashkin had published in his Nature paper. The problem with Nature at the time -- it's no longer true today -- but back then, there were almost no materials and methods reported in the papers they published. Believe it or not, materials and methods were relegated to the bottom of figure captions. So, every figure legend had, at the bottom, four or five sentences explaining the methods. All I had to go on was a few sentences and this diagram, which, of all things, showed a negative lens in front of the microscope with laser entering, of all things, the eyepiece! Well, that's kind of weird, because if you're trying to look through the microscope, how would you do that if a high-power laser is shining into one of the two eyepieces? Did you have to look in through the other eyepiece, avoiding the high power laser beam somehow, or did you use a camera? Whatever. Ultimately, I threw out Art Ashkin's design, and instead tried to discover the basic principles of how the optics worked. And this, by the way, turned out to be a wonderful exercise, because being thrust on my own to learn is really how I first understood it. Stymied by Ashkin's obscure diagram, I went back to the drawing board and figured out how the optics needed to work. Actually, it sounds pretty simple: all you have to do is produce a diffraction-limited focus of the laser in the specimen plane of a microscope, and that would trap things, if the laser power was enough. In practice, however, you wanted to do more than that. You also wanted to move the laser focus around within a volume of your specimen: you wanted to move it left and right and up and down and in and out. But how, then, would you take a focus and move it? You needed some external optics to do that. It couldn't be the same optics that are used to focus the microscope, because the optical focus needs to remain fixed on the specimen, and you need to move the trap relative to that. So, you needed to build external optics that could scan and move the beam. The best ways to do this had actually all been worked out back when folks developed the laser-scanning confocal microscope, which was another Nobel prize-winning invention. The confocal microscope optics basically contained all the secrets of how you move a focal spot while maintaining the full optical aperture, so it stays diffraction-limited.

My study of all this led me to the confocal microscope, and a better understanding how I might accomplish it. So, I soon had it designed, and this was all in a matter of a couple of few days, tops, during which I went from reading Ashkin's paper to having designed my first optical trap. Except there was a problem. I needed to get a laser, I needed to buy all these lenses, I needed to buy these dichroic mirrors. I had to order all this optics stuff. But it took a while to get it in. I ordered it literally during my first few weeks at Rowland Institute. Thankfully soon, the stuff came in, and I started putting it all together on a very nice Zeiss microscope that they already had at the Institute, and which I’d basically commandeered for this work. It all went together amazingly quickly. I think I had my first trap assembled within a day or so. I had all the pieces put together, but there was one problem, which is that I didn't have a specimen of E. coli to trap to test it. Why? Because Howard Berg was still in the process of moving his own lab across the country from Caltech to Harvard. The moving truck carrying his lab equipment, along with his bacterial strain collection, had only just disembarked at Harvard, and they'd just stuffed a freezer full of these frozen strains. If I was to use 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 thaw and culture the strain, wait a couple of days for it to come up, and so forth. So instead, I used a trick that almost every microscopist knows. When you can't find E. coli, use another bacterial strain. (laughs) I took a cover slip out and I scraped it against 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 come off. But you'd be totally wrong. The plaque of your teeth is home to a zoo of perhaps a dozen different bacterial strains, a few of which actually are highly motile. Some of them are long and thin, some are short and fat, and a lot of them look a bit like E. coli, but they're not. Still, they swim around like gangbusters. And so, I re-suspended this little white glob that I’d scraped off my tooth in some saline buffer, put it under the microscope, and sure enough, I saw lots of things swimming around. And, after just a bit of alignment, my optical trap worked! I was able to trap and arrest the cells, and move them around at will.

To me, this was fantastic. At the time, I’d rigged an external lens that moved around, and the motions of that lens would produce motions of the diffraction limited laser spot within the specimen. I dubbed this the “Optical Etch-a-Sketch,” because I turned one knob (attached to a micrometer attached to a lens) to move left and right, and another to move up and down. You could turn the knobs together, and you could grab a single bacterium and make it do a square dance, by turning the knobs in succession in different directions. I thought this was the greatest fun ever. I was visited shortly thereafter by a guy named Stephen Smith, who's today a famous neuroscientist. He works at the Allen Brain Institute today in Seattle, and he used to be at Stanford, and before that at, at Yale. He was a Howard Hughes investigator. Steve was an old buddy. He dropped by to visit me, and he was astonished that he could not only capture a bacterium, but by turning the knobs just so, you could write your name with the bacterium (laughs) under the microscope, and record it all on video.

So, the optical trap came together, and it was a beautiful thing. The next thing to do was to calibrate it, to figure out how much force it was generating, and then do some actual experiments. I spent the next year and a half or so doing several trapping experiments using bacteria, studying properties of their flagella filaments. The flagella of bacteria are not directly connected to the motor itself. Instead, they’re attached through a short, flexible coupler which acts something like a U-joint, so that the filament can be rotating on one axis, while the motor that drives it can be pointing in a somewhat different direction, that is, it can communicate power off-axis. These things work a lot like those little bendy plastic soda straws we used to have, which had a flexible accordion pleat near the top, where you would bend the straw. If you turned the bottom of such a straw while you held it firmly, the upper part would rotate too, but it could go around a 90-degree turn. Bacteria have a flagellar component that works essentially like that accordion pleat, and it's called the “hook.” With the optical trap, we were able to measure the elastic properties of the hook, showing that it would first flex rather easily in one rotational direction, but then, it would lock up more stiffly and communicate torque. It had just the right mechanical properties for a U-joint. This was one of the very first measurements at something close to the single-molecule level using an optical trap. The flagellar hook is actually composed of about 200 individual proteins, so this wasn't quite a single molecule experiment. But this was really a warm-up experiment for motors.

I spent the next year or so trying to show that you could attach beads to individual kinesin molecules. I did this work in collaboration with Bruce Schnapp, who had been at Woods Hole and was one of the original co-discoverers of kinesin. At that point he'd moved to Boston University. I also worked with Larry Goldstein, who was an assistant professor at Harvard (now at UCSD), who was also very interested in kinesin. We all got together at the Rowland Institute. They supplied the protein, I supplied the optical trap, and we ran the assays together. We were successful in getting single molecules of kinesin to move our optically trapped beads. Soon thereafter, I began to measure the forces, the velocities, and so forth, and everything was off and running. Ultimately, it turned out that kinesin was a great molecule to work with. After showing that you can get single molecules to move, and measuring the forces they produce as a function of velocity, the next thing was to ask, "Well, do they move in discrete steps? Could we measure the fundamental events associated with these motors?" It had been long hypothesized, since they move along polymeric filaments, that motors like kinesin and myosin might hop from one subunit of the polymer to the next -- or perhaps jump over several at a stroke – and that this would comprise the fundamental step. It was thought that myosin moved in discrete steps, and it was thought that kinesin moved in discrete steps. But no one had ever measured any of these directly (there has been many indirect attempts), and it was an outstanding question.

So, the Great Step Hunt started. At that point, my lab had been joined by a very talented grad student from Harvard named Karel Svoboda. Karel is pretty famous in his own right today. He works at the Janelia Farm Research campus of the Howard Hughes Medical Institute, and has pioneered the use of two-photon confocal microscopy for studying live neurons and synapse formation. At the time, Karel had joined the Harvard biophysics program and was working with Howard Berg, who brought him over to meet me at the Rowland Institute. I also worked with German postdoc named Christoph Schmidt, a biophysicist who was also captivated by the problem of how to measure molecular steps. To hunt for steps, we needed something in addition to the optical trapping apparatus, and that was some way to measure the exquisitely small displacements that would take place within the trap zone. So basically, you need to build a “nano-meter”: you need a measurement device that is sensitive to really, really tiny displacements. Today, there are at least four or five good ways to do this, but at the time, I was casting about for the best approach, and I came across the work of a guy named Winfried Denk, who is today a Max Planck Director in Munich, and before that in Heidelberg. Denk is well known as the co-inventor of the two photon microscope, together with Watt Webb at Cornell. At the time, Denk was a grad student at Cornell. He was an immensely creative guy, and we really hit it off: he became a friend for life. Back then, Denk was interested in how hearing works. We have these specialized structures in our ears called hair cells. The hair cells vibrate when they're driven into motion by the surrounding structures and fluid, which is in turn pumped by the tiny bones in our middle ear -- the hammer, anvil, and stirrup, all connected to the ear drum. Whenever the hair bundles, which project from the hair cells, are displaced, they transduce this motion into a tiny electrical impulse. It was known that when you moved the hair cells by a bit, a small current would flow into the cell, so they must be opening channels of some kind, and they were exquisitely sensitive. Denk wanted to know what fraction of the overall motion was actually transduced into an electrical signal. Why? Well, because we can hear very acutely -- and some organisms can hear even more acutely – so it was thought that displacements might be registered right down to the level of Brownian motion. Put another way, that our hair cells were so sensitive that the random thermal motions of their hair bundles at body temperature was sufficient to modulate the flow of ions across the cell membrane, which ought to be measurable. But if that's true, you might be able to carry out the following experiment. You could measure the random, Brownian excursions, corresponding to exquisitely small displacements, at the nanometer level, and simultaneously measure the cell’s electrical output. And those two signals should be tightly cross-correlated. Right? The more you move, the more voltage you get. So, Denk set about building a displacement meter, because he needed to measure that Brownian motion.

By that time, I guess it was back in 1976, Neher and Sackmann had received the Nobel prize for their successful recordings of single ion channels opening and closing in cells. So, the technology had existed for about ten years for measuring the picoamperes of current that flow when channels open up. But the real challenge was to measure nanometers along with the picoamperes. Winfried Denk figured out a clever way to do this using one of the imaging modalities of the light microscope. Light microscopes were revolutionized, first by the invention of phase contrast, for which Zernike got the Nobel prize in physics, and later, by Nomarski and others, including Smith, who first developed what's called differential interference contrast microscopy, or DIC. This modality is particularly well-suited to work with digital video, where you can play with the gain and the contrast. DIC works by a kind of wavefront shearing, using different polarizations, and when the waves scattered by the specimen get recombined, depending on their polarizations, they give you shades of grey (light intensity) that correspond to tiny differences in optical thickness in the specimen. But they also will change the shades of grey in a way that reflects tiny differences in displacement, as well, provided that you're in the right position with respect to where the wavefront shearing is taking place. Denk modified a DIC microscope, by not sending through a wide mean of parallel light across the whole aperture, which is called a Köhler illumination. Instead, he focused the light of a laser to a tiny, diffraction-limited spot in the specimen plane. This corresponds, as you know, to a spot that’s roughly the size of the wavelength of light, and it’s the tightest focus you can achieve: a spot about a micron across. Within that spot, you have two beams with orthogonal polarizations, which are very slightly displaced from one another; split by about a tenth of a wavelength. If there was an object within that diffraction-limited spot that scattered light and moved, it would tend to favor one polarization versus the other. You could then tease apart the blended polarizations using a quarter waveplate, and look in two different polarization channels, call them channel A and channel B, and compute channel A-minus-B over channel A-plus-B, to get a differential measurement. Denk’s modifications turned normal DIC optics into a displacement meter. When the object moved a tiny bit, it would favor one polarization versus the other, resulting in a small change in the ellipticity of the light that emerged, was mainly circularly polarized, but with a little bit of ellipticity. By building what is essentially an ellipsometer, Denk could measure that tiny displacement through the change in the overall polarization of the light that came out. Denk built his instrument and discovered that, lo and behold, the hair cell in the ear transduces about 75% of its signal into an electrical signal when it's being driven by Brownian motion alone. Put another way, the hair cells in our ears are tweaked to nearly the physical limits of perfection. You can't do much better than that, because if it were any better, all we’d manage to hear would be random noise.

In some sense, this is the auditory equivalent of a very famous experiment done by Hecht, Shlaer, and Pirenne during World War II, showing that our eyes can register single photons. I've actually written some articles about the physical limits of sensory transduction, pointing out how many different senses, for example, electroception in sharks, magnetoreception in bees, vision, hearing, taste, have nearly all been tweaked by evolution to approach the physical limits of perfection. Of course, you have to estimate what those physical limits might be, and so forth, and so it's an interesting and complex topic. But when I wasn't doing kinesin research, I was captivated by this other stuff.

Now, back to our story. I realized that in many ways, the optical trap that I’d built was very much like the device that Winfried Denk had built. Denk's device used a red laser: a He-Ne laser. In fact, it used the same type of laser that was used at the time in supermarkets, for scanning at checkout. Today, of course, they use red diode lasers, but back then, checkout stands had these He-Ne lasers. I didn't want to use red light, of course, because it was damaging to a lot of biological specimens. But I realized that the key aspect of Denk’s work was it employed a diffraction-limited spot. I thought, "But an optical trap is also a diffraction-limited spot!” It's just at enormously higher power, and it's in the near infrared, at around one micron wavelength. Therefore, if I tweaked the optics of my own microscope just a bit, and I introduced the so-called Nomarski prisms used for DIC imaging, so that I sent in light, not in one polarization but in two orthogonal polarizations, to form that same diffraction-limited spot, then I could build what I called an “optical trapping interferometer.” It would simultaneously function as an optical trap and as an interferometer that could report on displacements down to the nanometer level. Casually, around the lab, we called this thing the “Denkometer.”

Zierler:

Did you know it had this duality from the beginning, or you discovered this later on?

Block:

Absolutely, from the beginning. It wasn't even a discovery, I’d say. I was casting about for ways to measure displacements, and one of the ways in those days was to simply image your bead, or whatever it is you're looking at: you can, for example, image the bead onto a quadrant photodiode, and watch it move from one quadrant to another by looking at the quadrant voltage signals. Or, you could image it on a detector array. A lot of people were using these linear arrays, with about 256 tiny photodiodes in a row. Of course, an array is pixelated, limiting the resolution. The quad photodiode is an analog thing, but it has a singular disadvantage, namely, that with an image cast onto the photodiode, if the photodiode itself shakes due to vibration, then the signal you record is indistinguishable from your object moving. So you have this problem with noise. With a quad photodiode, any vibrational movement of the detection arm of your microscope was indistinguishable from the displacements that you were trying to measure. And if you're trying to get down to the nanometer level, or today, to the picometer level, that noise was going to be a real problem.

So, I was casting about for ways that were less sensitive to ambient noise coming from the apparatus. It turned out Denk's interferometer, which he'd built in Watt Webb’s lab for looking at hair cell motions, was, in fact, independent of vibrations of the detection arm, and depended only on motions within the focal spot itself. As I mentioned, I also realized that this spot could also function as an optical trap. If you had some object in the trap, if the trap beam wasn't particularly stable -- let's suppose the trap moved a little bit, left or right – then it would simply carry the trapped object with it, and then you wouldn't get a signal. The signal only depended on the motions of the trapped object relative to the trap position. Not in absolute space. So, you were relatively immune to two major sources kind of experimental noise. You're immune to the trap wandering a little bit. We're only talking fractions of a micron, but still, that's a problem when you're trying to measure nanometers. You’re also immune to vibrations of the light sensor. I realized that Denk's device could be adapted, and that instead of using a red detection laser, I could simply use my high-power trapping laser and “recycle” the light. I would use its infrared light once for the trap, and then I'd capture that same light as it emerged on the condenser side of the microscope, and send it off to my polarization detector.

So, we built the optical trapping interferometer in, I think it was 1991. And within a year, we’d obtained measurements of kinesin-coated beads where we were able to see the individual steps that kinesin took. And those steps turned out to measure eight nanometers each. They corresponded precisely to the distance subtended by the dimeric subunits of tubulin, moving from one dimer to the next along the microtubule. So, it's as if kinesin were walking down a sidewalk, stepping from one paver to the next. That was the first direct measurement of steps by a molecular motor. Since that time, other researchers have looked for evidence of substeps in kinesin motion, still others, including my own lab, have carefully measured the timing of the 8-nm steps: these turn out to be distributed in interesting ways. At low kinesin concentrations, you can watch when single molecules step, and their steps are exponentially distributed, in other words, they step at random times. You can correlate the transitions of kinesin molecules through the stepping cycle, for example, by using different ATP analogs, which can cause it to slow or stall out in different parts of the cycle. There are lots of great experiments possible: hundreds, in fact, that have been done on kinesin since that time. A great many rely on the ability to visualize these steps.

It turns out that under some conditions, the left step and the right step, so to speak, take different amounts of time, on average. We can get kinesin to limp, so it takes a fast step, that is, a short average duration step, and a slow step, of longer average duration, in strict alternation. That finding argues that the two heads of kinesin, which is a two-headed beast, alternate as it moves forward. This strict alternation in stepping was something stemmed from that work. The proof that kinesin could work in the single molecule level also stemmed from that work. The force-velocity curve of kinesin stemmed from that work. And quite a number of experiments since that time, performed by my own group and several others. Kinesin is the founding member of a superfamily of proteins. There are perhaps 14 different classes of kinesin. And in any cell of your body, there are perhaps half a dozen different kinds of kinesin molecules that are being expressed at any given time. These kinesins all carry out different tasks within the cell. Some kinesins transport vesicles, some separate chromosomes, some ferry RNA transcripts, some move mitochondria. Kinesin motors get harnessed for different tasks at different times in your body. It's since been possible to explore some of the different classes of kinesin, which exhibit different mechanical properties. They spend different amounts of time in different parts of the mechanochemical cycle. They produce different stall forces. They move at different speeds. All this has been enabled by optical trapping technology.

A few years later, we got rid of the optical trapping interferometer, and adopted a simpler technology, which is based on that same quadrant photodiode I was mentioning before, where send the light scattered by the bead onto the quadrant photodiode. But by now, we were able to get around the problem of the vibration of the detection arm by using a clever optical trick which was suggested to me by a postdoc of mine, named Koen Visscher, originally from the Netherlands, and today a professor of physics at the University of Arizona. Koen also got excited about optical traps when Ashkin first published about them, and Koen had built one of the very first traps, when he was still in grad school at the University of Amsterdam. He’d invited me to Amsterdam to serve on the committee for his thesis defense, and I got to know him better there. I was impressed, and I invited him to do a postdoc with me. He came to work with me first at the Rowland Institute, and later moved with me to Princeton University. Koen had the insight that instead of looking at an image of the bead on the photodiode, we should arrange the optics so that the photodiode was focused on the back aperture of the condenser of the microscope. When it's focused at that plane, it's not seeing the light distribution that corresponds to an image of the bead. Instead, it's seeing a light distribution that corresponds to the Fourier transform of the bead image. So, the back aperture of a lens, in Fourier optics, contains that transform. It's not quite a perfect transform: that depends on strictly paraxial rays and things like that. But to an excellent approximation, the back aperture of a microscope holds the Fourier transform of the specimen. It so happens that a translational displacement (i.e., movement) of the object in real space corresponds to a change in phase in the Fourier transform. As long as your detector is a bit larger than the size of the light distribution its capturing, then it won’t matter if your detector jiggles a little bit left and right, or up and down. You could still measure the light, and the signal that you get is independent of that jiggling. 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 no longer give a signal.

This approach came along as second great way of detecting nanometer-scale displacements. To this day, we use either a quad photodiode, or similarly, something called a PSD, which is a position-sensitive detector. It's another kind of silicon or germanium device that allows detection of position. By employing one or the other of these methods, you can achieve nanoscale measurements of objects in optical traps, and you can make those measurements with great precision. We eventually got to the point where we could measure the motion of the bead to within an angstrom, and make that measurement on the order of 50 times per second. Of course, a physicist will speak about the bandwidth of a measurement. It's not very sensible to talk simply about just a single measurement, because you could take any noisy measurement (one that has zero-mean noise, that is), and you could measure it many times over to average out the noise and improve your estimate, right? So the real question is, well how fast can you do it with a given precision? And so, what you’re really asking for is the power spectrum of the device.

I'm fast-forwarding now to many years later, because shortly after the kinesin steps were discovered, one of my expert colleagues (who I will not name) came to me and said, "Well, if you can do that, can you measure the steps taken by a polymerase moving along DNA, as it goes from base to base?" Now, those steps are expected to be about 25 times smaller than the kinesin steps! And measuring down to just eight nanometers was the state-of-the art, back then. I mean, that was the cat's whiskers, and I didn't really think we could do a whole lot better than that. Anyway, I sat down and did another back-of-the-envelope calculation. I knew what the stiffness of the optical trap was, which essentially acts like a simple spring. I knew the optical stiffness. I knew the sizes of displacements that we were looking for. I knew the temperature, and so I knew what k_BT was, the thermal energy, so I could figure out what the Brownian noise level would be. And I asked myself if I could make the trap any stiffer, since there are practical limits to how stiff you can make it. You do this by increasing the light level, but if you increase that too much, the optical trap becomes a device for “opticution,” a colorful word coined by Art Ashkin. It heats up and destroys whatever you're looking at. Another problem, of course, is that if it becomes so stiff that, during the course of one step, it manages to exceed the stall force of the motor, then the protein won't move. So with kinesin, there's a stall force, which lies in the range of 6 to 8 piconewtons. For instance, if the force of the trap increases by more than 8 piconewtons within a single step of 8 nanometers, it won't move at all, thereby limiting the trap stiffness to lie below 1 pN/nm. There are these limits to how much force you can produce. There are the limits to how much light you can use. There are limits to the stiffness. There are limits, also, to the temperature and how much it might be raised. I managed to convince myself, based on a simple back-of-the-envelope calculation, that it would not be feasible to push the measurements of protein motions down to the angstrom level. I was pretty thoroughly convinced by this. But, as it turned out, I’d produced right solution, but it was to the wrong calculation! The reason I was doing the wrong calculation is that I was thinking about a purely stationary optical trap, with the bead at its center.

A few years later, my group invented a different device, which is something called an “optical force clamp.” An optical force clamp is an optical trap that changes in such a way that the force on the object that it's trapping remains constant, independent of any movement. One way to achieve this is to build a sort of trap follower. As soon as your object starts to move, you move the trap right along with it, always keeping a certain fixed distance between the trap and the object, either leading or following it, depending on whether you wanted to apply a positive or negative force. That's like stretching a spring to a certain extension, and when the object moves, you maintain the stretch in the spring by moving the far end of it, as necessary. But there's a catch with that method, which is that you can only know when the object's moved by continuously measuring its position, so you know when it’s displaced. Each measurement of position takes a certain amount of time, because it's a noisy signal. And you may have to average over several cycles, perhaps, to figure out that it's moved a tiny bit. Then, you have to build feedback loop, which signals when to move your trap. Of course, you have to have a way to move the trap. And how are you going to do that quickly enough? We used these things called acousto-optic deflectors, which can bend light beams very fast. But not infinitely fast. So, you can move the trap quickly, in principle, but you also have the loop closure time of that feedback cycle, which limits how fast you can go with a force clamp. And for some of our experiments, that was just too slow. Nevertheless, the use of a force clamp has one very special advantage, which is that all those pesky stiffness terms that I was talking about earlier, in my original calculation, just drop out of the problem. It turns out that the amount of displacement that you have to impart to your trap in a force-clamped situation, in order to keep things at exactly the same force, corresponds exactly to the distance that the trapped motor steps. You can easily see why. And there's no limit, at least in principle, to how small a step you can record this way. You're no longer limited by the kinds of things that limited you before. So it would be possible, at least on paper, to measure angstroms with that approach. The real problem was with the loop closure time.

So, fast forward to the 2000’s, when we finally solved that problem, too! The way that that problem got solved resulted in the only Physical Review Letters paper that I’ve ever published. (both laugh). A way you get around the loop closure time problem is with something called a “passive force clamp”. I’ll try to explain how it works. It turns out that optical trap, when you think about it, acts like a potential well. And any potential well, sufficiently close to the bottom, always looks like a parabola (considering two dimensions, for now). A parabola produces a harmonic potential. And that means, of course, means that the force follows the behavior of a simple spring, because the derivative of a parabola is a straight line, and that gives Hooke's Law. That's why the force goes up linearly with the displacement as you move an object out of the optical trap. But there comes a point when you get nearer to the edge of the trap, where eventually you can just pull the object out of the trap altogether. And beyond that limiting distance, there's no restoring force at all, because you're fully out of the trap. So the parabola, which is the basic energy profile, rises up, but it must ultimately depart from that shape and flatten out completely. And the force, which is the derivative of the energy, rises up, but then it drops right back down to zero again: if you're well outside of the trap, there's no force. So, by continuity, that implies that somewhere near the edge of the trap, there’s a spot where force must stop growing altogether, and go flat, before dropping down again. In other words, the force goes through a maximum. So, if you could somehow take your trapped bead and move it out to where the force goes flat, it will have a constant restoring force applied to it. That is, for any small displacement about that point, there's no variation in the restoring force. So, if one were to displace the trapped bead a little to the left or right from that spot, it would experience no difference in force. But that's exactly what a force clamp does! A force clamp is designed so that when you move an object, the force is adjusted to remain constant.

In summary, an optical trap acts just like a force clamp in a small region located at the outer limb of the trap, were the force goes through its maximum. This is what we call a passive force clamp. The beauty of this is that it doesn't depend on using feedback at all. In some sense works, it almost infinitely fast, or more accurately, it works at the speed of light! The only problem with a passive force clamp, insofar as there's any problem, is that the region immediately surrounding the force maximum of a trap is not very large. You might think it would be too narrow, but it’s plenty wide enough for registering angstrom-sized displacements. The reason for that is that the trap potential changes on the scale of the wavelength of light, which is around a thousand angstroms. So, we only need the force to remain reasonably flat -- say, to within 5% -- over a region of perhaps a few nanometers. And so, the passive force clamp was invented. My grad students, Elio Abbondanzieri (today, at Univ. Rochester) and Will Greenleaf (today, at Stanford Univ.), and my postdoc Michael Woodside (today, at Univ. Alberta), were all heavily involved in this development. To get it to work, we needed a double tweezers arrangement, so we could use a DNA or RNA tether to pull a bead out into the clamp region of the opposite trap. In other words, we placed optical tweezers on either side of the molecule, and so we could use one of the two traps to pull the bead out into the constant-force zone, where it was passively clamped. By the mid 2000’s, we were able to watch a single molecule of RNA polymerase (RNAP) take steps along a DNA template as it transcribed the RNA for a gene. The individual steps that it took measured 3.4 angstroms each, which is precisely the distance that Watson and Crick had derived in their Nature paper of 1953, based on the X-ray structure of the double helix.

Our measurement was important in a lot of ways. Not only was it a crowning achievement for measuring small displacements using optical traps, setting a record that stands to this day, but it also allowed us to rule out one of the candidate mechanisms for RNA polymerase that had been proposed. A well-known biochemist named Mike Chamberlain, at U.C. Berkeley, had argued for a so-called "discontinuous elongation” model of RNAP, wherein it would translocate in a series of jumps, corresponding to the small loops of DNA that it would take in, transcribe into RNA, and release. Those loops would be of variable size. It turns out nothing of the kind takes place. The polymerase enzyme literally moves from one basepair to the next, stepping along the “rungs” of the DNA ladder, one at a time. Not only that but, we were able to measure the force velocity relationship for RNAP. The shape of that curve told us something about the way in which the molecule spent time in its post-translocated state (i.e., after a step) versus its pre-translocated state (before a step). Without getting too technical, it told us a lot about the mechanochemical cycle of RNA polymerase as it synthesizes RNA. We learned a whole lot, in fact, from those experiments. It wasn't just about being able to see a truly small displacement. It was more about trying to parse more information out about the molecular mechanism by which RNAP works. Also, together with my two terrific collaborators of long-standing, Jeff Gelles (at Brandeis University; we were in grad school together) and Bob Landick (at the University of Wisconsin-Madison, one of the world’s greatest experts on RNAP), we’ve published a slew of papers since that time, about such topics as the effect of various protein co-factors on transcription, and on the effects of different sequences on the template DNA itself, which can code for RNAs that contain elements like terminators or hairpins. Polymerase exhibits a very sophisticated behavior. It can back up, it can arrest, it can pause, it can terminate. This work was all enabled by optical trapping technology, and being able to measure motor displacements with high sensitivity in real time, all at the single molecule level.

Zierler:

Wow. (laughs) 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?

Block:

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 be coming in less and less, and eventually he was bedridden at home and near the end. He passed away in the Spring of 1991. There was a sea change at the Rowland Institute after that. His son-in-law, the person I’d mentioned earlier, who’d rowed for Harvard and, I suppose, fancied himself a sort of gentleman-scientist, was raising Morgan horses on his private estate in New Hampshire. But he would come in once a week to the Rowland Institute and attempt to run things. Things went fairly smoothly for a little while, but he was too out-of-touch with the workings of the place. For reasons unknown to me, Howard Berg was passed over, and not named next director of the Rowland Institute. So the direction--

Zierler:

He wanted that? As far as you knew, he wanted that title?

Block:

Absolutely, Howard had wanted that title. He occupied the largest office at the Rowland Institute, and he also ran one of the largest and most productive research labs. And I worked closely with him. Berg had been under the working assumption that he was being groomed for the directorship after Land, and he’d even told me as much, particularly at the time when he recruited me from Stanford to join him in Cambridge. And, of course, he also had another research lab and group over at Harvard that he maintained, and so he had something to fall back on, so to speak. I probably shouldn't phrase it as "falling back on it" (laughs) because most scientists aspire their entire careers to have something like that. But Howard has continuously maintained his lab at Harvard, and he continues to do very well to this day, even as he approaches 87 years of age. Important scientific contributions continue to pour out undiminished from him, even to this day, which is downright amazing to me. But they didn't cut Howard’s ties to the Rowland Institute, so he still maintained an effort there. But the directorship never transpired. Also, I should point out that there were a few people who’d been hired by Land at the Rowland Institute who were not especially productive. Berg had been very successful with his work on visualizing flagella using fluorescent methods (pioneered by Linda Stern, his longtime lab associate), and by inventing a new way of applying torque to tethered cells using something called electro-rotation. Then, there was also our collaborative work on using optical traps to study flagella, too. Also successful was another group, spearheaded by a researcher named Dongmin Chen, working together with his Harvard mentor, Jene Golovchenko: they’d built an early scanning tunneling microscope that could work at liquid helium temperatures, and were doing very interesting things with that on silicon crystals. There was also a Danish scientist, Lene Hau, who’s today a full professor at Harvard. Lene and her co-workers became famous for building apparatus to produce a Bose-Einstein condensate, then using that to slow down the speed of light in the material to approximately the speed of a bicyclist. Today, she can nearly stop light (and trap quantum information) altogether, with the right refractive index and the right optics in the right medium. So, some great science came out of the Rowland Institute in my era, but there were also a bunch of ne'er-do-wells that weren't doing very much at all, and had been hanging around the place for years. It was hoped by some of us that the new management would replace these individuals with a generation of eager young scientists who might be more productive, but that never really came to pass. The climate was very uncertain at that point, because Land’s son-in-law didn't seem to be very invested in the running of the Rowland Institute. Scant attention was paid to the day-to-day activities, and almost none (apparently, from my perspective, anyway) to the longer-term trajectory. No one was willing or able to confront any of the festering issues. And right around then, I received a job offer, entirely unsolicited, from Princeton University, to join their Molecular Biology Department, with a joint appointment in the Princeton Material Institute.

Zierler:

Sounds like it was great timing for you, also.

Block:

Yes, it was great timing. You know, I was damned lucky, because nearly everything I'd tried at the Rowland Institute had seemingly turned to gold. (laughs) You know, they say that chance favors the prepared mind. I'm not exactly sure how prepared my mind was, though. I just got very lucky. I also worked very hard, but I was fortunate to have been in the right place at the right time, with the right people and the right support. I could do research without teaching or writing grants, and this allowed me to be more productive, without question. I was able to achieve a good many of the things that I dreamed might happen when I was a still postdoc at Stanford, working on myosin. In particular, my dream experiment of finding motor steps, which was something I'd thought about over a decade earlier in grad school, had come to fruition. Of course, the angstrom-scale steps of polymerase along DNA hadn't yet been seen: those wouldn't be measured until over a decade, after I’d moved back to Stanford. But while I was still at Rowland Institute, the kinesin steps had been published, and this was an important advance. To this day, aside from various reviews, it’s my most-cited paper: there are over 2,000 citations to that paper at this point, which, for biophysics -- an obscure little field -- is a lot.

Zierler:

Yeah, right.

Block:

The steps of kinesin certainly counted as significant work at the time, but what really sweetened the pot for Princeton was that they were offering me an associate professorship with tenure. And here I was, in what amounted to some type of glorified postdoc, at the Rowland Institute. I hadn't spent five or six years somewhere as a stressed-out young assistant professor. A tenured job at Princeton University sounded awfully tempting to me.

Zierler:

Yeah, right.

Block:

On the other hand -- and one of the reasons, here again, that I got lucky, is that I actually managed to meet the formal qualifications for that faculty job at Princeton. I got lucky because purely out of personal interest, I’d been volunteering to teach an undergraduate class at Harvard on sensory transduction, which is one of the themes we already talked about. The reason I was teaching that class at Harvard in sensory transduction harks back to my grad school experience in Colorado, as I mentioned, were we invented a course in bioenergetics and taught it. I thought it was just cool that students could teach their own classes, if they worked at it and got inspired enough. And so, I was teaching this course at Harvard, sort of to keep my oar in the water, and perhaps to polish my explanatory skills. But when it came time to compile a case to get the approval for a tenure decision at Princeton, they wanted to know all about my teaching experience. If I had just worked at the Rowland Institute, I would have never been able to get tenure at Princeton. And instead, I got lucky, and I had something to show them. Another aspect of being lucky is that Harvard had something called "CUE Guide" (today, it’s been renamed to the “Q” Guide), which was a compilation of undergraduate course evaluations. My course managed to get a great score in the CUE Guide. The only person in the sciences who scored better than me, at the time, was Nicholaas Bloembergen, a Nobel laureate who taught a very famous course in quantum mechanics. But I’d received the second-highest score, so I was kvelling (laughs) about that. My Harvard teaching record duly got sent off to Princeton, and their Appointments & Promotions Committee approved me for tenure. So then came a big decision point for me. Truth be told, I necessarily keen on decamping to Princeton, because, after all, look at the deal that I already 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’d asked for (within reason, I suppose), the Rowland Institute bought for me.

Zierler:

And was your position, did you have a level of job security that as far as you were concerned was equal to tenure?

Block:

Well, yes: you’ve placed your finger right on the sticking point. The problem was that, what had been tacitly understood -- although never written down in any contractual way -- was that every scientist hired by Edwin Land at the Rowland Institute enjoyed lifelong job security. Or so it seemed, anyway. It didn’t appear that Land had ever fired anyone. And most of the research staff were too young to retire. But clearly, that could not be the case, because by this point, a year or two after Land had passed away, one or two people had been eased out, under the aegis of his son-in-law, probably for not having contributed very much. But it wasn't very clear to me whether there was any direct correlation between how well you performed and whether you’d be kept on, or not. Nor, for that matter, whether there was anything resembling tenure at the Rowland Institute. It was equally unclear to me on what basis any salary raises or various types of promotion were be based, because this place was neither a part of traditional industry nor a part of academia. It was this unknown entity that ran according to its own, obscure rules. I finally had an opportunity to have a sit-down meeting with the acting director, Land’s the son-in-law, whose name was Phil Dubois, (pronounced doo-boys; he died in 2014). I met with him, and I said something to the effect of "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 many friends here. I have all these local collaborations in place, at Harvard, MGH, and BU. I have a steady supply of great grad students coming from Harvard. Academic life in Cambridge is hard to beat. My work is sufficiently high-profile now that postdocs are writing me letters and asking if they can work with me.” So even though the Rowland Institute was somewhat isolated, for the reasons we've already talked about, it looked like I had a great thing going, with a lot of scientific momentum. And so I asked Phil to please come clean with me: “All I really need to know is, can I expect any kind of job security here? Can you commit telling me, in broad strokes, what's going to happen with the Institute over the next two or three years? Are you planning to fold the place? And does the Rowland Institute have the funds in its endowment to keep going at its current pace, or will those funds be spent by some date? Are you planning to make Howard Berg the next director? Are you planning to award something like tenure to the folks here who perform up to some standard?” And so forth. I--

Zierler:

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.

Block:

Once again, yes, you've put your finger on the crux of the matter. That was precisely it. Sadly, it turned out, the bottom line was that Phil DuBois was completely unprepared, or perhaps unwilling, to answer any one of my questions. I suspect he was unprepared, as you may have inferred, because he himself had not decided about the future of the Institute. He himself had no real notion of what was good or bad science. He had not decided what to do about Howard Berg. And so forth. I think, on some level, he was just looking to get himself out from under the burden of running the Rowland Institute, which he’d inherited pretty abruptly. He never struck me as being particularly invested in it. Which is a shame.

Zierler:

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?

Block:

Yes.

Zierler:

Okay. It sounded like that. I wanted to get your answer, we can deal with that later, but you know.

Block:

You may keep it in the transcript.

Zierler:

Okay.

Block:

So, fast-forward a few years. After that meeting with Phil DuBois, my decision was pretty easy. I moved to Princeton in 1994 and assumed a tenured faculty 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.

Zierler:

Which was probably interdisciplinary at birth?

Block:

Yes, interdisciplinary at birth, but there's more to it than that, and we'll get into it in a moment. A few years after I left Cambridge, it turns out that Phil Dubois decided to step down from the day-to-day management of the Rowland Institute, which he never had his heart into, anyway. He appointed one of the long-time internal researchers, a physicist named Mike Burns, to take care of the operations as a kind of acting director. Now, Mike Burns is a smart scientist, but he is not a manager. Eventually, Land’s family decided to unburden themselves of the Rowland Institute, and they shopped it around. In the end, they basically gave it to Harvard University. The Rowland Institute that still exists today is now run by Harvard University. But it's a very different place from the time when Land walked its halls. I mean, architecturally, it's the same building, and it's a very beautiful place, mind you, but it's run by totally different rules and in a totally different format, with a totally different budget. Looking back, I was there for its a real heyday: a flame that burned brightly but briefly, in which some fabulous science happened in a short time, from several groups. Nothing like that has happened since, to my knowledge.

Zierler:

So the professors there now are Harvard professors?

Block:

Yes, they are. The place is mostly populated with a bunch of postdocs, who are Rowland Fellows. They use it for a Fellows program now, where they bring in sort of super postdocs. But they work under very different rules and conditions. They have much less space; they don't have unlimited budgets, they’re more bounded by the things that they can do. They're there for comparatively short term. Lab space is at a premium. And the person who runs it reports to Harvard. So it's a completely different place, with a different ethic and a different feel to it. The Rowland Institute of today is not the Rowland Institute of its heyday while Land was still alive. I was able to experience it in its last years, as the personal playground of Edwin H. Land. And it was quite the place. As I said, a whole lot of terrific science came out of it. There was Howard Berg’s work on pattern formation by swarming bacteria, and on the physical properties of the flagellar hook, on the electrorotation of motors, as well as fluorescence work on visualizing individual flagella. There was the scanning tunneling microscopy of silicon and germanium surfaces of Dongmin Chen and Jene Golovchenko. There was some nifty work on optical binding forces, by Golovchenko, Mike Burns, and Jean-Marc Fournier. Lene Hau, with Mike Burns and Jene Golovchenko, made Bose-Einstein condensates and made ”slow light.”

So, there was good stuff happening all the time. But there was also some weird stuff. There was one computer information guy who was basically strange. There were other people there who were far, far less productive. I used to call it Lotus Land, you know, as in the Odyssey? There is both an advantage and a disadvantage to being in a place where everything you want is available to you. The obvious advantage is: you can do anything you want. The less obvious disadvantage is: you're also free to do nothing. And there's something a little bit terrifying about being bounded only by your imagination, which can sometimes spiral away. I know it sounds silly. Most scientists I know are pushing hard against various constraints. They only wish that they could have an extra $50,000 to buy that laser, or only wish that they could do this or that, and everything would be so much better. When if all that happens, the fact of the matter is, you're now limited by your own thinking, and your ability form collaborations, and your ability to come up with clever ideas. That can be flat-out terrifying! And so, the Rowland Institute was great for some people and terrible for some others.

I credit Howard Berg again for helping me succeed at the Rowland Institute. I went through a period in my life, back in grad school, when I was mainly goofing off and not getting a whole lot accomplished. It was Howard Berg's letter to me that caused a personal “phase transition,” where I finally buckled down and did some actual work. Doing so, I discovered that if you succeeded in a small way after a little bit of work, that could lead to more successful work, and that would lead to even more successful work, and then finally, you'd have something significant to show for it. This is particularly true in graduate school, but it’s been true throughout my life. You know, the first extra hour you spend, nearly nothing of note really gets done, and then another extra hour, a little bit gets done. But scientific progress is totally non-linear. After a certain point, all of-a-sudden, things start to really take off and interesting results come in increasing frequency. Personal productivity is just not related in any simple way to the amount of effort you put in. Particularly all those extra hours. The extra time only paid off, usually, at the very end. And often, in some unexpected way, too! But I’d had a taste of that in graduate school, and I realized that if I worked hard enough, maybe I'd get lucky, or maybe luck would emerge, somehow, for my efforts.

In any case, something good would happen. And here, all around me, I had all this intellectual inspiration. I had the work of Edwin Land, I had the work of Art Ashkin, who invented the optical trap. I had the work of Winfried Denk, who invented his clever interferometer. I had Howard Berg, who’s been a one-man institute of science, on bacterial chemotaxis and motility. And another individual, whom I haven't even talked about yet, was Ed Purcell, who won the Nobel Prize in Physics, too. Purcell is perhaps best known to physics students worldwide for his masterful textbook on electromagnetism, in the famous Berkley series. Howard Berg enjoyed a long-standing scientific relationship with Purcell, and together, they’d written a seminal paper on the physics of chemoreception in bacteria, which led to Berg’s famous little book, “Random Walks in Biology.” Purcell was a true polymath, with contributions to nearly all branches of physics. It was Howard who first hooked me up with Ed. I got involved with them both (which thrilled me no end, since I was in awe of Purcell). Through the two of them, I also got to work with a young Harvard undergrad named Mark Schnitzer. Mark later won a prestigious Goldwater Scholarship, which, I believe, is awarded to the most promising young scientists, mathematicians, and engineers at Harvard. Mark was so bright that he solo-authored paper in Phys Rev E about chemotaxis while he was still an undergraduate. That work involved a theoretical analysis, using some advanced math that I couldn't even approach myself -- so my hat's off to Mark! In his free time, Mark worked with Howard, Ed, and me on some the physics of bacterial chemotaxis. Mark selected Princeton for grad school. This turned out to be a terribly fortunate choice for me, because Mark eventually became my graduate student after I, too, moved to Princeton, a year later than Mark, as a faculty member.

There's one particular paper that I'm especially proud of, which emerged from our time together at Harvard, the so-called “four generation” paper: a paper co-authored by Ed Purcell, Howard Berg, myself, and Mark Schnitzer. Each of its four authors was in a different scientific generation, and each one served as a mentor to the next. It's a wonderful paper that laid to rest some popular fallacies about chemotaxis. Purcell’s interests ranged over absolutely everything, as you can imagine. He owned one of the first generation of Macintosh computers, a little baby Macs with floppy disks. It came with a simple, but slow BASIC interpreter that you could program. But Ed Purcell could somehow do more to model bacterial motion with interpreted BASIC on a Mac than most people could manage in that day with a supercomputer. Of course, this involved some of his famous back-of-the-envelope calculations, which allowed him to simplify some of the fabulous complexities of bacterial motion, and capture the essential physics in just a few simple equations that he could simulate in (nearly) real time on that slow Mac. He was able to take what was, in principle, a challenging computer simulation problem, and then turn it into an elegant (and deep) mathematical problem. This was the kind of inspiration I had around me when I was at Harvard! I had colleagues like Ed Purcell. I had Bill Press, of Numerical Recipes fame, who at the time was at the Harvard-Smithsonian Center for Astrophysics. He's since moved to Texas. I had David Corey at MGH, who I’d known from my grad school days at Caltech; a brilliant neuroscientist. And, of course, I had Berg himself. All around me where these amazing people, so it was hard to leave the Rowland Institute. It was also hard because it meant striking out totally independently, without so many friends and colleagues. In some ways, it was intimidating, and in some other ways, it was rewarding. But I knew I would have to write grants, and I have to get them funded successfully, and I knew that I would have to recruit new students and postdocs.

Zierler:

What about building a lab? Were they doing that for you, or you had to do that also?

Block:

Yeah. Well, they built me a lab, but they did it pretty much on the cheap. One other downside of Princeton is that they were offering me a position and prestige, but they weren't offering me a whole lot of start-up support. Neither did they offer me a large salary. In retrospect, I was pretty naïve about such things, so perhaps I should have been tougher in my job negotiations. I’d had no experience in those. Not that I felt that I had much leverage, though. I eventually discovered that a good many of my former students, when they graduated from my group. were receiving between two to ten times the amount of startup finding that I got from Princeton. (both laugh) And this was just three or so years later, so it was not some inflationary trend that accounted for the difference. Princeton had really given me a lowball offer. On the other hand, I was permitted to bring with me a lot of optical equipment with me from the Rowland Institute. 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 attract strong grad students like Mark Schnitzer. And I told you about Koen Visscher, who arrived from the Netherlands. Another postdoc who joined me at Princeton was Tom Perkins, who today is the Director of JILA at the University of Colorado. Tom Perkins already had experience with optical trapping, having done his graduate work at Stanford working with Steve Chu, who later got the Nobel Prize for his work on atom cooling. Tom also knew about me because his father served in JASON, a group of academicians with high-level clearances that consults for the U.S. government every summer on technical issues related to national defense. I, too, was serving in JASON, and I knew his father from our summer work, which was conducted in La Jolla, CA. Once summer, Tom came down to La Jolla for to visit and I took him out to a nice seafood restaurant in La Jolla. There, I weaved my web and convinced him to do his postdoc with me. Which he did, and he did a great job. So, too, did Matt Lang, who is one the faculty at Vanderbilt University, today. I would attribute the largest part of my scientific success to the people that wound up in my lab, partly through academic connections, partly through friendships, partly through reputation, partly by happenstance, and partly by osmosis. I mean, no great lab was ever really built without lots and lots of folks contributing. A lab group is like an extended family, and it develops its own internal culture. Insofar as I've been successful, it's because I've had some truly talented, hard-working people walk through my door. I'm very proud of the fact that three of my former students are professors today on the faculty at Stanford University. And several others are professors on the faculties of other great universities, too. I suspect that there may only be a handful of other professors at Stanford who can make an equivalent claim about their former students. Of course, I can only take indirect credit for this. These people got where they are by virtue of their own intelligence, their own diligence, and their own accomplishments.

Zierler:

But they are probably beneficiaries of your mentorship and the way that you had two incredible mentors.

Block:

Yeah, but it's most definitely a two-way street. I mean, yes to all that, but yes also to the fact that my science benefitted so much from them, and there's a kind of synergism that develops. I was mentioning before about how a little bit of effort doesn't really get you anywhere, but the growth with additional effort becomes non-linear. I think the same is true for scientific collaborations. A little bit of collaborative work, and you get a little somewhere. A little bit more, maybe you get some more. But if this ramifies, if this really gets going, you reach a point where you spur each other on to a level that you wouldn't have achieved without the other. Over the years, I think I've been not just inspired, but in many ways challenged, by my best grad students and postdocs, to do better than I might have otherwise. And sometimes, I’ve experienced it a bit like a friendly competition, to see who can advance the project more. Looking back, I'm really grateful for all that. And as I said, partly, it's that I’ve just been fortunate, and it’s partly because success builds success, like rolling a snowball down a hill. Getting the snowball going in the first place can be damned hard, but once it gets going, it's gratifying to see what can happen.

Zierler:

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?

Block:

No, unlike Princeton, which more-or-less just happened, Stanford did not go that way. I have another long story that goes with that. It was never quite intention to move on from Princeton. I would have been happy staying there. You know, in Princeton, you're within spitting distance of New York City, and all that has to offer. You're at one of the top universities, with arguably, one of the best physics departments anywhere. I had strong colleagues and so forth. But what I really wanted to do was see the field of biophysics grow and prosper at Princeton. And that meant bringing some physicists with similar interests into the physics department. I actually had a couple of friends and colleagues working in the area, who were superb. For example, at Bell Labs (later renamed Lucent Technologies), there was David Tank, who did neuroscience. Or at the nearby NEC Research Institute, which was founded by the NEC Corporation, and inspired in many by the model of Bell Labs (Unfortunately, NEC pulled the plug on the Research Institute in 2002 and turned it into a corporate lab). Over at NEC was an incredibly smart theorist named Bill Bialek, who had interests in biophysics. So Bill Bialek was nearby, and so was David Tank, and also some others. I wanted to bring them to Princeton. And I also wanted Princeton Physics to hire some junior faculty in biophysics.

For a few years while I was there, they held searches in the Physics Department for junior faculty. And it was very frustrating for me, because time after time, an excellent biophysics candidate would come for a job interview. A few of them gave wonderful, inspiring lectures. Then, then the time would come for the assembled physics faculty to consider whether to offer a position. The unusual way that Princeton would do this is that all the faculty would meet around a large table, and instead of discussing the candidate in any kind of open forum, they would literally go around the table, one person after the next, and each would speak about the candidate, with little dialog or rebuttal: by and large, there were few interruptions and even fewer questions. What might typically happen is the first individual would say, "Well, I went to the seminar and I'm no biophysicist, but I thought it was really interesting." The next person would say, "Not only was it interesting, but I got a chance to interview the candidate, and we found that we had a lot of science to talk about." The next person would say, "We not only had a lot to talk about, but I was amazed at how much general 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 some of the technology that this candidate uses might be useful in my own work. We already have in mind a collaboration if they were to come here." This would just sound better and better as it went around the table. But 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 those three words would damn the appointment. Absolutely kill it.

The Princeton Physics Department paralyzed itself for a period of years that way, convinced that biophysics wasn’t a valid branch of physics. They did have people like Stan Leibler and Bob Austin on the faculty, who advocated for some field they preferred to call "biological physics,” and not biophysics (to me, this was downright silly). Or maybe it's physical biology? But is biological physics, or physical biology, in some fundamental way different from biophysics, I ask? Perhaps they were parsing their words in an effort to distance themselves from the folks in the Biophysical Society, whom they were not so fond of, and who tended to worked more on things like protein structure or spectroscopy? While I think it might be worthwhile trying to draw a disciplinary distinction between purely structural biology, such as crystallography, cryo-electron microscopys, NMR, and suchlike, and other types of biophysics, the kinds of distinctions they seemed to be drawing were, to my mind, not very helpful. and certainly not conducive to the enterprise of recruiting young, interdisciplinary talent.

Zierler:

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.

Block:

Absolutely. Once again, David, you see the cultural problem. And not only is that true, but it's also true that biophysics is one of the most quintessentially interdisciplinary sciences that exist. You need to know something about two vast fields, biology and physics, and be able to work at their intersection. Trying to draw hard perimeters around this stuff is counterproductive. Real biophysicists, in my opinion, don't care at all about these boundaries, whether they’re truly disciplinary, or merely linguistic. The last thing they want to be doing is trying to define themselves with new vocabulary. So, I think the term “biological physics” was created more for marketing to physicists than for anything else. If you interview people, you'll still find lots of physics types who claim to be doing “biological physics” and somehow want to explain to you how 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.

Zierler:

Right. (laughs)

Block:

Anyway, back to our story. I got increasingly frustrated that Princeton physics seemed utterly unable to make a new hire, in either biophysics or biological physics. And there was another thing that discontented me, which is that for a number of years, I’d hoped to be put up by the university for a Howard Hughes investigatorship. These position were gold. The HHMI Foundation would give you a fabulous level funding, and you wouldn't have to apply for smaller grants constantly. You were relieved of a certain amount of teaching duties. You got an administrative assistant who was paid by HHMI, and who worked exclusively for you. It was the cat's meow. As you may know, the HHMI was funded from the estate of Howard Hughes, and he’d originally set it up as a tax shelter during his lifetime, with negligible payout. Thanks to a change of law by the U.S. Congress, the HHMI was forced to divest itself of a certain amount annually of the fortune that it had once squirreled away. They were required to spend something like 5% per annum, and that instantly turned them into one of the largest benefactors of biomedical sciences in the world.

So, I wanted to become a Howard Hughes investigator. Two or three of my -- well, let's call them competitors -- in the single molecule biophysics field, already held these prestigious Howard Hughes professorships. Even three of my former students held them. But there was a problem, which is that back in those days, HHMI had ways of restricting the number of applicants. Instead of being able to apply on your own, your institution had to put your name forward, and apply on your behalf. On top of that, universities were restricted to submitting just one or two applicants. You essentially had to win the sweepstakes at your home university before your name would be considered by HHMI. So, at a place like Harvard or Princeton or Stanford, your real competition wasn’t nationwide, but instead from colleagues at your own university who wanted to get ahead of you in line for that HHMI nomination. This got decided by chairs and deans, and it quickly became more political than merit-based. In those days, if you were at a top-ranked university with many great candidates, an HHMI nomination alone often translated into winning an award. Deans would do things like promise HHMI nominations as part of retention or recruitment packages, in fact. And HHMI kept changing the rules in every competition for these awards. At the time when I first sought a nomination, HHMI had the sort of arrangement that I just described. However, in the year that I was hoping to get my name put forward for it, HHMI announced that they would prefer to review more candidates who were women. So, I found myself on the wrong side of the gender divide on that. Princeton, following the suggestion of HHMI, decided to go a woman candidate, instead of me. I’d been the first in line, so to speak, but I got passed over. Unfortunately, this turned out badly, because the woman candidate whom Princeton put forward ultimately failed to win an HHMI award (her portfolio may have been a trifle weak, or so I thought.).

Meanwhile, and ironically, Ron Vale, one of the co-discoverers of kinesin, who was on the faculty at UCSF, also wanted to apply for and HHMI investigatorship. He managed, based on a retention plan, to convince his own university to put his name forward, even though they were favoring women that year. And Ron won it. I found myself in the unpleasant situation where I couldn’t manage to get my name placed into the HHMI competition, but a male rival could. It was disheartening. It was around this time that Stanford Applied Physics came calling, and told me that they were interested in hiring me. What was attractive about their offer was twofold. One was that I would be appointed jointly in both the Biology and Applied Physics Departments. Since I've always had a leg in both disciplines, that was appealing. The other is that they proposed to site my lab in the Biology Department, which was fabulous, since most of my students come from physics, but they need ready access to shared biology equipment, things like centrifuges and autoclaves and cold rooms, and suchlike. That way, if their protein preps failed, they could easily walk down the hall and find someone more knowledgeable to help them. Students isolated in a physics building under those conditions are much harder-pressed to move forward. So, I wanted my lab in Biology, but I wanted my main appointment in Applied Physics, which is where my primary appointment is held at Stanford. That way, I could recruit students from the physics side and then train them on the biology side. Stanford was offering exactly what I wanted.

Zierler:

But they got it, obviously. There was no issue like at Princeton about is biophysics a real thing. There was none of that?

Block:

They totally got it. But here's another irony: after I left Princeton, kind of in a huff because of their failure to promote biophysics, you know, and because of their failure to let me apply for an HHMI position, they founded the Lewis-Sigler Institute, which is for biophysics. On top of that, the Physics Department hired Dave Tank from Bell Labs, and they also hired Bill Bialek from the NEC Research Institute. And later, they hired my own former Stanford grad student, Josh Shaevitz, to be part of the Physics faculty. In fact, he’s done very well there, so I guess that’s a sweet form of academic revenge. But all that happened after I left. I’d lobbied hard for biophysics, seemingly without effect, when I was there.

Zierler:

Steven, could I just interject here? Because there's one thing that's curious to me. I mean, the mid-90s, 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.

Block:

Well, I have come to believe that the Princeton Physics Department is rather parochial. And my view, these are not decisions that are being made by folks charged with a broader view of the sciences. They are decisions being made at the departmental level by, you know, journeyman physicists, with little-to-no experience of biophysics whatsoever. It's really hard to nucleate something when you haven't got any good example of it in the department. They did have Stan Leibler there, but then, Stan eventually left Princeton, before I did, for Rockefeller University. This was partly because, I’m pretty sure, Rockefeller promised him funding so that that he’d never have to write a grant again as long as he lived. Stan was also entertaining an offer from the EMBL in Heidelberg, Germany. In fact, Leibler cultivated lots of outside offers when he was there: he always seemed, to me, to have one foot out the door. I'm not sure if he ever truly fit with the Physics Department there, nor vice versa. And there was also Bob Austin, who got his doctorate with Hans Frauenfelder at the Univ. Illinois. Hans was, as best I can determine, the originator of the term “biological physics,” which he used to characterize his own work on protein conformational states, presumably to distinguish it from the things all those other biophysicts did. Bob is good scientist, but a strange bird. He tended to work nights and was rarely seen by day; his wife really ran the lab and had a stern reputation. I don't think he ever really had the ear of his colleagues. I certainly can't argue that it's in some way because I left, but after I did, I think there may have been a shift in some attitudes. Maybe a conversation was spurred by the fact that both Leibler and I decided to leave Princeton, or perhaps there was just a growing sense that things needed to change. It suppose it’s possible. And maybe it was all the publicity associated with the success of the Human Genome Project, as you intimated? Regardless, I wasn't around for that discussion, and therefore can't speak to it. But what I can say is that all the movement towards establishing the Lewis-Sigler Institute, and all the associated biophysics hires, happened after I left. Had it all been initiated before I made my decision to leave, perhaps I might have stayed at Princeton, rather than moving to Stanford.

Stanford, by the way, also lured me with the promise of an HHMI investigatorship, but that never came to pass, either! Once on campus, they, too, passed me over in favor of another colleague. So, I lost out on that round. Furthermore, by the time the next round of HHMI nominations came up, I’d aged out under their ever-changing rules, and was now considered to be too old to apply. These days, you apply for and HHMI position in an open competition, without requiring your university to pick you. So, they lifted one of the barriers that had stymied me, but only to introduce another.

Zierler:

Steve, a quick request. As we get to Stanford, a quick narrative break, and a request for a biological break.

Block:

(laughs)

Zierler:

We're at three hours and I'd love a few minutes.

Block:

Oh, my God. How has the time gone?

Zierler:

We're going strong. How about we take a couple minute break and we'll resume then. Is that good?

Block:

To pee or not to pee, that is the question!

Zierler:

There you go. (laughs) Alright, I'm back. Alright.

Block:

To quote from the opening act of Hamlet, "for this relief, much thanks."

Zierler:

That's right. (laughs) Okay, so. Palo Alto, here you go.

Block:

Palo Alto, here I come. The year was 1999. I was at Princeton from 1994 to 1999. With some regret, I said goodbye to Princeton. They did promote me to a full professor there, although that promotion hadn't come with much of a raise. Another reason for going back to California was that Stanford was not only willing to fund the construction of a new, low-noise/low-vibration lab for my nanoscale work, but it was willing to give me a decent raise in salary. So, my wife Kathy and I, and our beloved golden retriever, Sophie, moved across the country to Stanford in the Fall of 1999. I was able to establish a good-sized lab, because there was quite a bit of space available in the basement of the Herrin Laboratories building, which nobody else really wanted. My office had no windows, but I was pretty used to living in a basement by then, given the needs of my research. Herrin Labs was the oldest biology building in Stanford, and it was absolutely perfect for the single-molecule work that I do, which is very sensitive to ambient noise and ground-borne vibration. You want to be situated well away from any roads and traffic, and you want to be in the basement of a building, where the vibrations of the main superstructure are not a problem. This building was perfect for that. It was an old type of construction, made of brick and mortar: the kind that promptly collapses as soon as there's an earthquake! Modern buildings are built instead to bend like bamboo in the wind, so that when the earthquake hits, the building has give. But that's precisely what you don't want for nanoscale measurements, because the floor is always shifting around a bit, whether you want it to or not. What you really want is the old kind of brick or stone building that will collapse the moment the Big One hits. It has the advantage that until the Big One strikes, it's relatively free of any vibration. On top of all that, this building had a berm surrounding it on two sides, was built on bedrock, and it was well away from traffic. The space I occupied had also had a “slab cut” performed, which is to say that they’d cut the concrete floor slab away from the supports of the building, so that it floated, unconnected, on the underlying earth. This cut had been done, I was told, because somebody had been working on ants in the space previously, and apparently, ants are extremely sensitive to ground vibrations, as well.

The bottom line is that they moved me into a fabulous space for nanoscale work in biophysics. They built a lab exactly to my specifications. Furthermore, they built it on time and on budget, which is a good thing. It only took a few months after we got there before everything was working beautifully. Of course, you also need the space to be temperature-regulated, too. If there's a fraction of a degree of temperature differential across the room, the metals from which the apparatus is made (including a microscope and other optics) will expand or contract, and they can move at angstroms per second. So, if you're trying to measure angstroms, you're out of luck if there's a thermal gradient. You need a temperature-stabilized, vibration-isolated, sound-proofed cleanroom to do the kinds of work that we do. It had a cleanroom-style entrance, with a gowning room and sticky pads on the floor, and acoustic isolation pads inside. It met the OSHA NC-30 noise standard, which is not quite quiet enough to hear a pin drop, but more akin to a quiet bedroom at night – but without my snoring. And so the Stanford lab was duly built, and it was in that lab that we were ultimately able to measure the 3.4 angstrom steps of RNA polymerase moving, one basepair at a time, on DNA.

Zierler:

So you're a happy boy at this point?

Block:

I was a happy boy at that point. Everything was going pretty well until about two, three years ago, when everything started to go south. Everything was fine until Stanford decided to embark on a wholesale campaign of new construction all over campus. They have lots and lots of money at Stanford, and they decided that the best thing they could do with it was to build lots of new buildings. I’m fond of saying that Stanford has an “edifice complex.”

Zierler:

(laughs) Right.

Block:

One of the problems is that, next to the lab where I worked, was the Old Chemistry Building. It was one of several original Stanford buildings, built from limestone around 100 years ago. This includes the picturesque buildings that form the colonnade around the Main Quad. Old Chemistry had been damaged, but not destroyed, in the Loma Prieta earthquake of 1989, which was roughly 30 years ago. It had been closed up and fence placed around it. They couldn't re-open the building until they fixed the damage and brought it up to code. And they couldn't bring it up to code because it was a chemistry building, and modern chemistry buildings require fume hoods, epoxied floors, certain special types of lighting and electricity, and so on, so they don't blow up or pollute. All sorts of precautions. But they couldn’t tear the building down and start fresh, either, since it had been designated as an historic landmark. So, there it sat there unused for many years until Stanford decided to turn it into a teaching and learning center, instead. That transformation involved taking the building, gutting its entire insides and turning it into a shell, and then building a 500-seat auditorium underneath. So, you can easily imagine the amount of earth moving involved to do that. And this is all taking place within 50 feet of my lab, just outside the Herrin building. The noise and vibrations were absolutely hideous. They were so bad that you could place a glass of water down on our conference room table and see ripples on the surface. You didn't need any special instruments that can detect nanometers to see it. The noise levels were so high that there was no way we could carry out any of our nanoscale measurements. But it was all going to be okay, they told me. I’d reached an understanding with Stanford that they would pay extra money to the construction firm, which would start its work at four in the morning, or thereabouts, and continue up until noon. Then, they would stop construction for the day, so we would have the afternoons free to do our experiments and collect data. That sounded acceptable to me, and we even shook hands over this agreement.

But as soon as the construction started, almost from day one, it was clear that they weren't going to abide by the agreement. At first, the workers stopped digging at noon, but then needed to put move all their bulldozers away, and that meant an additional hour of heavy vibration. And before we knew it, they were working until three, four, and five in the afternoon, and there wasn't a damned thing that I could do about it. I lodged repeated complaints with the construction supervisors, and also with the university overseers of the construction, but to no avail. I started writing letters to my deans. It wound up that the only times when we could collect data were either during the nights or weekends. We eventually lost the weekends as well, because construction fell behind schedule, as it does, and they started working on the weekends to try to make up time. So that left only the nights: you had to work after dinner until dawn. My students didn't want to do that. I didn't want to do that. I went to my dean and said, "Look, we had an agreement." The dean decided that Stanford was hemorrhaging money by paying for the construction to start early (which hadn’t worked out), that construction, evidently, had a higher priority than my research. So he thought that what Stanford would do instead is give me some extra money. If they gave me that extra money, I could give all my grad students and postdocs a raise. And presumably, if I gave them a raise, maybe they'd work nights. Ha!

Zierler:

Wow.

Block:

I thought the whole idea was laughable on the face of it. You even laughed. I didn't need to tell you where this was all going. You can easily imagine. It did not work. Some of my students would work a few nights. I mean, nearly all graduate students have the experience of pulling the occasional all-nighter. This is perfectly normal.

Zierler:

But not as mercenaries.

Block:

Exactly. But not as mercenaries, and not as their only mode of working, right? These people have lives to lead, after all. They have boyfriends or girlfriends or spouses and they want to go to the movies and they want to have a social life. Some of them lived in San Francisco and needed to commute, but the commuter train doesn’t run late at night. For a variety of perfectly good reasons, grad students will not work exclusively on a night shift. And they didn't sign on for that in the first place. So, what happened was that my lab started hemorrhaging people. The postdocs would quit, and the grad students would graduate out early if they could. No new student -- for a period of two or three years straight -- not one single grad student volunteered to rotate into my lab, because the word was out: if you want to work for Steve Block, you've got to work the graveyard shift.

Zierler:

And relocating was just not an option?

Block:

No, because Stanford had embarked on such a widespread program of construction that there were, at one point, no fewer than 14 different construction sites, located all over campus, going simultaneously. Not that I didn’t try hard to find a place to go. There was almost no building more than 800 feet from some major construction. So if you argue, "Look, my lab needs to be situated near a certain amount of bedrock, I've got to be a certain distance from any trafficked road, and I've got to be a certain distance from a construction site," there was literally no place on campus where they could move me. The entire Stanford Medical School, for example, was built on landfill from the old San Francisquito Creek, and most of their buildings are not suitable for my kind of work. The Physics Department, in the old Varian Building, had a bit of low-vibration space in it, and they did renovate that space for Hari Manoharan, who worked with scanning tunneling microscopes. But since occupied that space, so there was no space for me over there. Besides, Physics was not my home department, it was Applied Physics. Applied Physics controlled a bit of space over in the old End Station III at HEPL, but the university had taken that over for some administrative offices, and it wasn’t available. To make a 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 another sound-proofed, vibration-isolated, electrically-isolated cleanroom for our work. They had neither the budget nor the inclination do this, and regardless, I'd still be put out of work for two years.

Zierler:

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?

Block:

No groundswell, alas. In fact, the general silence was pretty disappointing. The one person who might have supported me was W.E. Moerner, a Nobel laureate in chemistry, who was also trying to carry out some single-molecule biophysics experiments in a nearby building. But he was doing what's called single-molecule fluorescence. This involves using a tiny fluorophore (a fluorescent chemical tag), whose image blooms out to the diffraction limit of the microscope and therefore looks to be, perhaps, 200 nanometers in diameter, and being able to carry out what's called “super-resolution microscopy”, which can pushes that limit down to roughly five nanometers, at best, and 50 nanometers is a more typical number. But even with super-resolution, that Is still an order of magnitude, or perhaps two orders of magnitude, bigger than the distances we were trying to measure in my lab. And so, none of these vibration issues turned out not to bother his group, in practice. In a phrase, he didn’t turn out to be much of a voice of support, because it wasn't his ox that was being gored.

Zierler:

So it was just yours, that's it.

Block:

It was just mine. Now, we jump to a year later, and comes the final blow, which is that they finally decided to build a new biology building. That was fine, but they also decided that the old building that I was in, Herrin Labs, would have to be torn down. And why did it have to be torn down? Well, Stanford has something called the GUP, or General Use Plan of Santa Clara County. Stanford has an agreement with the county, and even though it owns a great deal of land, only a fraction of which is occupied by the campus itself, it will only build a certain number of square feet per year on that campus. This, in return for permission to keep going, and to get various special favors from the county, such as building a road that would handle all the traffic going into Stanford. Over the years, for example, Stanford has made footpaths available to the community, and set aside certain areas as open space, under the GUP. The county has been very reluctant to allow Stanford to embark on any massive building programs on campus, for a variety of reasons, many of which are perfectly reasonable, because they don't want unbounded growth taking place within their community. Stanford University, along with its big hospitals and even the shopping center that it controls, represents the largest employer in the area, and it contributes hugely to the local traffic, and to the pollution, and to other bad things. So there's this thing called the GUP, which comes up every 10 or 20 years for renewal--

[End of first file, begin second file - 200609_1047_D]

Block:

--and it is a deeply political and widely fought. Residents go before the county supervisors to argue about the provisions, and the university's lawyers get up, and they carefully negotiate how many square foot Stanford might be allowed to build, say, over the next 10 or 15 years. In other words, is they exceed that number, then the only way to build a new building is to tear another one down. It was determined that the building housing my lab would be torn down, in favor of a new biology building, now called the Bass Building, and I was told that I would have to pack up all my stuff and move to the new building. But there were two problems with that. One is that they would have to outfit another specialized laboratory in the new building, suitable for nanoscale work. The other problem is that the experiments I do are performed on large air tables, of the type that you often find in optical physics labs. They're about a foot thick, and about ten feet long, around six feet across, and they weigh a ton. On them are mounted all manner of optics, microscopes, and lasers, and so on. You can't get them one of the rooms in the basement without removing all the parts bolted to the top of the air table. That means dismantling all the carefully aligned optical apparatus, which in many cases took years of work just to construct, then re-assembling them at the new site and taking around a year to align, calibrate, and get things working properly. I had custom apparatus running in four different rooms, and it took the better part of the decade to build it all. And it would all have to be torn apart, to free up the air tables, so they could be turned sideways and maneuvered through the doors, into some freight elevators, and across to the new building. In one case, they actually had to demolish a portion of a wall just to get the air table out. What all that meant, of course, is that whoever worked in my research group would not only have to take everything apart, but would also have to put it all back together again. Nobody in my group wanted to have that kind of interruption in their graduate or postdoctoral career. No one wanted to go through any of this in the first place. So, by the time I was forced-marched into the new building, nearly everyone in my lab had either quit or moved on. I can’t really blame them, either.

Zierler:

Steven, I'm wondering if at this point you were rethinking maybe following in your father's footsteps and doing theoretical physics. (laughs)

Block:

Yeah. Well, that's another bit of irony. I didn't mention it early, but I probably should have. Maybe you’ll want to move this into the earlier part of the transcript? My father retired from Northwestern as an experimental physicist in the 1970’s, and moved with my mother to Aspen, where he became a theorist. To the best of my knowledge, there are not many particle experimentalists who went on to do theory. Of course, there were a very few people who did both theory and experiment. Enrico Fermi, of course, is famously the last physicist who managed to be world-class in both areas. So, my father turned to theory, and for the next 22 years in Aspen, right up until his death at age 92, was doing theoretical and computational work, with four to six computers that he’d crudely rigged into a home network. In fact, during his last year of life, he managed to publish more scientific papers than I did.

Zierler:

(laughs) Wow. Physicists never retire, by the way. I've learned that.

Block:

I guess. Mathematicians, on the other hand, are not known for producing very much after the age of 35, which is why the Fields Medal has an early age limit on it. There are few notable counterexamples of mathematicians who contributed later in life, but not many. Physicist is kind of an open book. Hans Bethe was pretty active until the very end, for example. So were John Wheeler and Phil Anderson. My father's first paper was published, I think, in 1949, and his last paper in 2017, a year after he passed. That’s a span of some 68 years, which is an impressively long career. And at one point, the editor of Physical Review Letters wrote to him, saying that to the best of his knowledge, my father had the longest-spanning publishing career in the Physical Review of any author. I don't know if that's true or not, but the editor seemed to be under that impression.

Anyway, back to my story. They marched me into the new biology building last year, except there was yet another problem. The new biology building was supposed to be a so-called "green" building. That’s to say, it was supposed to reduce the energy used for heating and cooling, and not consume very much. This was a general requirement of the GUP, and also reflected Stanford's desire to reduce its carbon footprint. But my lab’s special needs got lost in communication somewhere, and for a variety of reasons, they failed to design the HVAC for my lab properly, despite the careful design I’d provided them, which they over-rode. The way that HVAC normally works is that you use chilled water, and you cool the air somewhat below the temperature that you really want it to be, and then you rewarm it with a local heater to exactly the temperature you like. Then, you can apply PID feedback control to the heating element and obtain very precise temperature control. This is a very practical way to maintain the temperature, which, for my nanoscale research purposes, needed to be clamped to within about plus-or-minus half a degree Fahrenheit, or a quarter of a degree Celsius. If temperature is not maintained somewhere around that level, you can get drift in the apparatus, due to thermal expansion. Well, they screwed up, big time, on this when they built the new Bass Building, by mixing the incoming air destined for my lab with other air meant for the rest of the building, instead of giving my lab a separate feed. They made a number of other design errors, too. But the net result was that to this day, fully a year and several months later, Stanford is still unable to regulate the temperature properly in the microscopy suite of my new lab. I've been left in an untenable situation where I have no students in my group, my apparatus is disassembled into pieces, and even if it could somehow all be put back together again, there's no opportunity for doing any new science, because they can't regulate the lab temperature. Now they should have--

Zierler:

So maybe coronavirus has not been so bad for you?

Block:

Well, the irony is that I experienced a “lockdown” well before any of my colleagues. And for longer, now.

Zierler:

(laughs) Right.

Block:

At this moment, due to the pandemic, we’re still locked out of our faculty offices and research buildings at Stanford. The new building has keycard access, and they’ve disabled all our faculty ID cards. But folks are slowly being allowed to return for short visits to work this week. I haven't been able to visit my new office there in nearly two months. Meanwhile, my lab’s computer server went down and won't respond to remote commands, so I’ll have to reboot something when I get back. Hopefully, it will still work when I do so [Note added in editing: the server died.] But Stanford has, unfortunately, really put the kibosh on my career. I’ve probably published my last paper on optical trapping. That pains me enormously. Of course, every colleague of mine has been experiencing a momentary stoppage of their research. But I've been going through my own share of difficult times for some three years now, with the lab dying a slow death of 1,000 cuts, as all my people leave. And now, with the destruction of my old lab and dismantling of my apparatus, I've been dealt a more-or-less permanent stoppage.

Zierler:

Whew. That's very difficult to hear. What, have you thought about leaving Stanford? I mean, is it easier to reboot somewhere else?

Block:

Well yeah, if I were 20 years younger, I might have told them what they could do with all construction, and left Stanford University. But there are several practical obstacles to that. One is that both my wife and I are approaching retirement age -- I'm 67 now. My wife runs the public library in Belmont, California, and she’ll be retiring in the Spring of 2021. Were I to move to another university, I would have to build up a research group from scratch, and probably find new funding (I’m on the last year of an NIH MERIT grant), and I would have to be there long enough to see a few graduate students through, so we're looking at least 6-10 years. But worse, it would take anyone about a year and a half, and perhaps two years, to build a lab with the type of noise isolation and temperature regulation required for my work. And of course, once I moved there, it would take another year or so to build new apparatus or to revive what I have. I mean, this is one-of-a kind, specialized apparatus that you don't just pick up and move. In fact, Stanford wasn't able to move it 100 yards into a new building. So, if I were 20 years younger, there's no question that I would have been furious at the outset with what Stanford did to me, and I would have left. As things now stand, though, I’ve indicated to Stanford that I will spend a year on sabbatical during this coming year. I’ve never taken a sabbatical in my career, so I’m long overdue. But the global pandemic has really dealt me a number on this. All my planned travel to visit colleagues in Europe is now up in the air. I was scheduled to take up a visiting professorship at Oxford University, my alma mater, during Trinity Term, but it looks now like that won’t happen [Note added in editing: it had to be canceled.] I'll return in 2021-2 for a year of teaching, next academic year, and then I'll have to go emeritus. It's been very rough for me this past year.

Zierler:

And emeritus for you, I mean, what does that even look like?

Block:

I don't really know. Well, of course, people keep talking about the "new normal" now, after the pandemic subsides. Like so many others, I really have no idea what this new normal will represent.

Zierler:

But there's no remote work for you if the heart and soul of your work is the lab.

Block:

That's exactly right. I mean, that’s the curse of being an experimentalist: you live and die by the equipment you have available, and by the experiments you can conduct. You also live and die by the people you have in your group, and the colleagues you collaborate with. The single-molecule research that my group does is not exactly the sort of work that an individual tends to do all alone. 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 students, and on collaborations. All of that has been blown apart by recent events, and I've been an unhappy camper for a while now. The best that I can hope for, now, is that I might contribute in some other ways to science. My wife keeps trying to get me to write a textbook, for example. I'm not sure I really want to do that -- although I did win an award for my scientific writing, once. (laughs) But that was a long while back.

Zierler:

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.

Block:

Absolutely. I think my research was sacrificed upon the altar of progress here at Stanford. I think that Stanford, in its headlong pursuit of ever-trendier initiatives, has failed to cater to its existing core faculty. The latest controversy at Stanford is they want to create an entirely new school: a School of Sustainability. One problem here is that no one can really agree on what “sustainability” actually means. I heard a lot of opposition to the idea among some of the faculty here, because although “sustainability” is fashionable topic, and the Development Office will have a field day raising money for it, it cuts across the existing departmental disciplines in ways that may well drive people apart, rather than bring them together. They're going to be cherry-picking faculty from various different departments and moving them over into the new school. The Biology Department, in particular, has some terrific folks who work in ecology and evolution, and it's not clear how or where they’re going to fit in this new initiative. Besides, Stanford University already has an interdisciplinary institute for the environment: the Woods Institute. Also, it already has an interdisciplinary institute for energy, too: the Precourt Institute. I think too much of this works to the detriment of the fundamental disciplines. We talked a lot about the fact that I view biophysics as a way of understanding, at a fundamental level, how biology works. And physics, I think, is the fundamental science. These are precisely the disciplines that, I think, get hurt when too many resources are diverted to support enterprises that, while they may have merit, lack definition and don't quite qualify, at least yet, as academic disciplines. If you really want to do science, and if you really want to understand how the world works, that's one thing. If you're more interested in social policy, social science, and in the applications of technology, then sustainability is probably as good an area as any! But you know, you’d asked before about whether I was personally interested in medicine. I’m certainly not opposed to medicine: I think medicine is wonderful. We need better medicine, better doctors, better healthcare. But that's not what I want to pursue. The world needs sustainability, and more to the point, we all need to worry about things like climate change and adaptability, and taking care of the Mother Earth by conserving resources. We need all of that. But that isn’t the discipline that I signed up for as a basic scientist. Speaking for myself, as that scientist, I want to understand how Nature works, not how we can work with Nature.

Zierler:

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 67, 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?

Block:

Well, yeah. (laughs) That is a viewpoint.

Zierler:

Right. (laughs)

Block:

I'm encouraged by your saying that 67 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--

Zierler:

What I mean to say by 67 is, you're a young 67, 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.

Block:

Oh yeah.

Zierler:

So the momentum of your 67-ness is young. That's what I mean. It's not an objective number.

Block:

Yeah, it's true. One can make the case, I suppose, that the more people in my age cohort who leave the system, the more available things will be for the younger generation. And a lot of that generation, because of finite resources, is being cut off. Millennials, in general, are not enjoying the lifestyle that my generation had, or even that my parents' generation had, before me. Arguably, my parents' generation did better, in terms of lifestyle and cost-of-living, than my own did. The next generation is doing remarkably worse. So maybe we need to make a place for the generation that's coming up. Viewed that way, perhaps my forced retirement is not such a bad thing, after all. It certainly feels like a bad thing to me, though. But whether it's a bad thing for society is a different question. You know, years ago, by a Supreme Court ruling, the United States stopped mandatory retirement in most areas. But it still happens in Europe, for example. And one of the consequences of that, maybe an unintended consequence of that, is a lot of European scientists facing retirement in Europe emigrated to the United States and finished off their careers here. So, we got kind of a brain drain out of that.

Zierler:

So Steve, let me ask you a question that could prove to be quite productive in the vein of if you were 20 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 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 30 or 40 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?

Block:

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 agreements with various deans and administrators and department chairs have all been oral agreements. They have been based on handshakes and trust. Many of these agreements 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. So much of the business they conduct is ephemeral that way, and it works to their advantage. The universities, when recruiting faculty, will often make certain promises, but I’ve had a career which was filled with various types of promises that go bent or broken along the way. That's not to say I'm not grateful for the work that I've been able to do, and all the support that I've been able to get, the talented students I've been able to attract. All that's been wonderful. But insofar as I've had problems, they've almost all been associated with various remonstrations that were made, which turned out, in the fullness of time, not to be worth anything. Stanford, as you know, built me this wonderful lab in 1999. But they also took away that wonderful lab! During recruitment, Stanford made me promises about being able to have certain nominations. Those didn't happen. So, several things did not to play out in the fullness of time, and I think it's partly because of the way that universities do business. Their goals and aspirations are not the same as those of their individual faculty.

One example of that is that we're required by law in California to undergo training in sexual harassment every two years. I must have a dozen such certificates on my office wall, having gone through many sessions of sexual harassment training every two years for 22 years straight. Originally, that training was more like a form of sensitivity training, about how important it is -- and I thoroughly agree with this -- to treat people with courtesy and deference and fairness. More recently, the sexual harassment training has morphed, in my view, into more about protecting the university against lawsuits being brought under Title IX, for various outrages performed by its faculty or administration that violate the law. It would appear that things are increasingly being written by lawyers, and they're being done to protect the university, not the faculty. And they are not necessarily being done for what I would call the right reasons, namely, that sexual harassment is 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 university administrations, increasingly, is that they seem more concerned about their image than they are concerned about what is right or 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. When I answered "get it in writing," what I meant by that is that if they make representations to you about various things, you need to get a written record of those, because the sources are not trustworthy. Even if the sources had the best of intentions, the fact of the matter is that in academia, there's a constant turnover. With all the personnel turnover, university administrations have little “corporate memory,” in my experience. They forget all the things they said they were going to do for you, and all the help they were going to provide, and so forth.

There was an example of this at Stanford I didn't even go into before, which is that I was attracted back to Stanford in 1999 because they had undertaken the creation of a new, interdisciplinary laboratory, that they called “Bio-X.” It was going to be housed in a brand new building, called the Clark Center, and they’d promised me, as part of my recruitment, that I would have a special lab built in it, for my nanoscale work. The laboratory in the Herrin Labs Building that I told you about earlier, by the way, was only intended to serve as a temporary space for six months after I got to Stanford, pending a permanent move into the Clark Center. Instead, I wound up working in the “temporary space” in Herrin Labs for some 20 years. Why? After all, I was supposed to move to this fabulous new lab associated with Bio-X. Well, when they finally built it, that lab too didn't fulfill the specifications. It was too small, and more importantly, it failed to meet the noise requirements. Fortunately, I had at least some of that in writing, and so I explained to the Stanford administration that this was not going to work. The deans scrambled for a while, but they eventually allowed me to stay on in the temporary space in Herrin, which met the noise and vibration requirements. So, this is the second time that Stanford tried to move me into quarters that would not have supported the kind of research that I do: first, around 2002, and later, in 2019. If I had moved into the new Bio-X building at the time, I would never have gotten my work done, and I would never have been able to measure those 3.4 angstrom steps as RNA polymerase moves on DNA.

Zierler:

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 30 year old in a new place with a brand-new lab that was essentially picking up where you left off.

Block:

I see.

Zierler:

What would you hope to accomplish in the next decade?

Block:

Thanks for clarifying that. In terms of my own research, there are a number of outstanding questions that I'd love to go after, right? In biology one speaks about the so-called “Central Dogma," which describes the flow of information from DNA, to RNA, to protein that makes possible all of life. Some of the biggest challenges in biology, arguably, revolve around questions of gene control. The difference between the tip of my nose and my liver and my bones is not that they have different DNA: that the same in every cell. The these tissues all have very different patterns of expression of that DNA, which lead to very different fates and very different trajectories. So if you want to understand life, then you really need to understand gene control. And there are quite a number of important enzymes that are involved in that. We talked about RNA polymerase, but there's also DNA polymerase and a large number of transcription factors, isomerases, gyrases, and so on. These are grist for the mill. All of these are proteins whose mechanisms are only poorly understood, and we'd love to understand how they actually work. We'd love to understand more deeply the mechanisms of gene control. There aren't just one or two mechanisms, but a great many, as it turns out. If you can think about a way to control genes, the chances are, Nature has figured out a way to do that and has already implemented it!

This topic worthy of an entire lecture, but I won't subject you to it here. If I had been able to continue with my research, 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 riboswitches. That's a term coined by my colleague Ron Breaker at Yale. The riboswitch turns out to be a very ancient form of gene control, and it predates, evolutionarily speaking, the type of control for which Jacob and Monod got their Nobel Prize, where proteins bind to DNA and repress or enhance its transcription into RNA. sitting as repressors on DNA and repressing genes. Riboswitches don't involve proteins at all. In fact, they probably predate the existence of proteins, and they may even predate existence of DNA. A riboswitch is composed of a piece of RNA that gets transcribed, but not translated. It sits upstream of the part of transcripts that are actually going to make proteins, and it folds up into a particular shape. That particular shape can bind to certain specific, small molecules, and it acts like a switch. Depending on whether or not it is bound to a specific small molecule, it can turn the downstream gene on and off. So it acts like an environmental sensor, functioning as a ribonucleic acid-based switch, or a riboswitch. My lab has been able to study how these things fold and unfold using optical traps. There's a whole world of riboswitches, and we were only just getting started on trying to dissect their mechanisms of gene regulation. We’d already written two or three papers on riboswitches, which continue to fascinate me. If I’d had an opportunity to continue, I would have certainly have done more with riboswitches -- and with the folding of nucleic acids into three-dimensional, functional structures, in general. And 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 puzzle. But that's was my passion, which, unfortunately, is being brought to a premature halt by forces beyond my control.

Zierler:

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.

Block:

That's an intriguing question. I suppose that I would push back a little, in the sense that it poses something of a false dichotomy. That the two are not mutually exclusive, after all. It’s true that there have been some highlights of my career, if you will, where we were trying to do something very specific and finally achieved it. That would include some of the highlights I've already talked about, such as seeing steps in the angular speed of the bacterial rotary motor, which told us something about how the motor must work. And seeing the first steps of kinesin along a microtubule, which also told us about how that motor worked. And seeing the steps of RNA polymerase along DNA, and so on. Finally, in more recent work, we managed to watch the folding and unfolding of nucleic acids, which can assume these very interesting shapes that are capable of catalysis, and in some cases, are responsible for a form of gene regulation. We can observe these little folding events as each segment of RNA snaps into place, making it a little shorter, and thereby measure what’s called the folding energy landscape. All of those things represented small breakthroughs in a practical sense, I suppose, and they certainly represented goals of the research, before we carried it out. We’d promised as much in several of my grant proposals! They became scientific accomplishments afterwards, because they managed to supply certain new insights. And in all cases, they pointed to new challenges for follow-up work.

So absolutely, it’s true that I could name four, or five, or six independent highlights during my career, each of which got me terribly excited about new prospects, renewed my spirit for scientific exploration, and kept me going for more years. In the retelling, I suppose we always have a warm spot our hearts about things like that. That's true. But it's also true that a research career has a kind of overall arc to it, in the sense that you alluded. I do consider myself, first and foremost, to be a biophysicist. And by that, I mean I want to use, not merely the techniques, but also the mindset of a physicist to address biological questions of interest. Maybe the real difference between a biologist and a biophysicist is not so much in the exact questions that they ask, nor in the systems that they study, but in the way they go about seeking answers. I have developed and employed technology that most biologists wouldn't easily manage or appreciate. In my line of 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, precision measurement. Phase-locked loops and stuff like that, you know, that most biologists don't get to hear about. And in my line of work, we also have day-to-day needs to run gels, clone genes, purify proteins, develop single molecule assays. And involves techniques that a typical molecular biologist also needs to know.

I think that one of the reasons that the students who come through my lab have been so successful in academia – in addition to being smart and talented, that is! -- is that they come out with considerable practical skills, and are ready for independent work. They can not only handle a number of things that only physicists usually do, but they can also handle a lot of things that only biologists usually 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 anything, it's that I'm part of a series of generations that, ever since the end of World War II, have shown that you can make serious inroads into biology from a physics perspective. Among the first generation were folks like Max Delbrück, who left physics with no training whatsoever in biology, yet made strong contributions culminating ultimately, in Max's case, with the Nobel prize. There were other Nobel prizes, too. Wally Gilbert is an example. He was a theoretical physicist who switched to biology, and who helped to pioneer DNA sequencing. And let’s not forget that Francis Crick, too, was a physicist, and he worked out helical diffraction theory, along with the structure of DNA. There's a generation of people in the 50s, going into the 60s, including folks like Seymour Benzer, Sydney Brenner, with strong physics or chemistry backgrounds, who made contributions to fundamental biology. The next generation after that included folks like Howard Berg. Then came my generation. Winfried Denk, who worked with Watt Webb at Cornell, is in my generation, and so is Carlos Bustamante, who worked with Ignacio Tinoco. We now we have a third or fourth generation of people, including many of Howard Berg's former graduate students, like Markus Meister, who's a neuroscientist at Caltech, Karel Svoboda, who's at Janelia Farm, and Mark Schnitzer, who's at Stanford. Some of them work in neuroscience, others in in biophysics. But they're all using physical methods, and have a physicist's perspective on measurement and observation, which they bring to bear on biological questions.

I'm part of a generation that's kind of carrying a torch in a particular direction, and I see a rosy future. My own research may be stymied for the moment, but I am fairly bullish about biophysics. It's still growing. It's been my privilege, for the last 20 years, to run the “Single Molecule Biophysics Conference” at the Aspen Center for Physics, held every other winter. Except in pandemic years, that is! Our conference has been oversubscribed in every single winter it’s been held. Arguably, it’s the most successful Aspen physics conference, insofar as we've raised the most money, we have the greatest attendance, and the field is going from strength to strength. As the co-organizer, with my former student Tom Perkins (now Director of JILA at the Univ. of Colorado), I've been able to see the field of single molecule biophysics grow from almost nothing. It didn't exist in the 60s. In the 70s, Neher and Sackmann showed that you could study single ion channels, and Berg showed that you could study single flagellar motors. But things were fairly quiet until the 1990’s. Since then, we’ve seen the advent a large number of ways of looking at single molecules, using fluorescence with super-resolution, optical or magnetic tweezers, scanning force microscopy, and more. Nobel Prizes were awarded for the development of super-resolution microscopy and optical traps. People now talk about carrying out single-cell PCR and looking at the genetic complement of a single cell. They talk about single-molecule protein and RNA folding experiments, and trying to understand how proteins and nucleic acids assume specific shapes to undertake chemical reactions. To my way of thinking, it's very lively field today. But it grew from almost nothing at the start of my career. So, my answer to the second part of your question is that I certainly do see a trajectory for the field, and I would characterize my own career as having made some meaningful contribution to that science. I say that with some immodesty, I'm afraid. Still, I'm very proud to be considered as one of the founders of the modern field of single molecule biophysics. I'm absolutely delighted to see what a strong field it is today, and how it's grown over the past 20 or 30 years to become a central branch of biophysics. I remember quite well when there were a mere handful of posters describing single molecule experiments at the annual Biophysical Society Meeting, out of something like 5,000 posters presented. Now, if you go to one of the annual BPS meetings, the mean-free path between single molecule posters is something like 20 feet, across the huge convention floor. There are literally hundreds of posters on single molecule biophysics. So that's been a sea change, and for me it's been a source of pride and gratitude.

Zierler:

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.

Block:

You know, mentorship is a funny thing. It's something of a moving toyshop, in my experience. I've been mentored in different ways. I mean, growing up as the son of a physicist, I sort of had a live-in mentor. But I took away, in certain ways, a negative lesson from that. There were certain things that I realized I really didn't want to do. On the other hand, it was part of my upbringing and it was instilled in me. I had this amazing experience from an early age, being able to meet and interact with some of the great scientists of our age. But that was 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 so I could work with him. He literally accepted a lectureship and turned his honorarium into a Steve Block fund, making it possible for me to come out to Caltech for an entire year. And he personally shepherded me into the field of biophysics. I have a debt of gratitude that I will never be able to repay. And not only that, Max literally arranged for my doctoral advisor. He picked Howard Berg and said, "This is the person I want you to work with." In some ways, he planned my career for me. I was young and naïve and contrary, but, for whatever reason, I didn't rebel against that. I went with it. But I had a lot to learn. A lot of scientists whom I’ve come to know, particularly at places like Stanford, Princeton, Harvard, and Caltech -- all the places I've been -- are pretty amazing people. They’re not just smart, but they have all kinds of other talents. Sometimes these are talents that they've never really tapped or deeply explored, but talents nonetheless. Some of them are great mathematicians; some of them are great chess players; some of them are great musicians; some are great mountain climbers. Simply exceptional individuals.

I think that what I learned, more than anything else, from my experience with Howard Berg, is that you can nurture the science in a person, but you can do it in a way that doesn't necessarily cut them off from all these other avenues. That you need to celebrate all aspects of people, and maybe you need to give them just enough rope so they hang themselves. But hope that they don't. Like all teachers, I've had my share of students who haven’t thrived. But those students of mine who have thrived did so because, I believe, I didn't micromanage them: I didn't look too tightly over their shoulders. I didn't go up to them every day and ask, "What have you done for me lately?" I like to imagine that they're going to be doing great things. We’ll meet, once a week or thereabouts, in group and private meetings, and we’ll talk about how things are going. But in retrospect, the students who've done the best with me 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. These were not one-dimensional characters who doggedly pursued science and little else. They were not obsessive. But they were polymaths, in more than a few cases. And if I look at the mentors whom I had, the Howard Bergs of this world, Max Delbrücks, the Ed Purcells, they’re also polymaths. Insofar as there's a pattern here, I think it's that science isn't just about something: science is about practically everything.

Zierler:

Yeah.

Block:

And so how can you to mentor so many aspects of a person? 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 that, "Education is seldom of much efficacy except in those happy dispositions where it is practically superfluous."

Zierler:

(laughs) Right.

Block:

So, you know, my father gave me all three volumes of The Feynman Lectures in Physics when I was still in high school. I really couldn't quite appreciate it then, but I started to read it more and more of it later. As you may have already heard, it's a book best enjoyed once you already know the physics, and aren’t actually trying to learn it afresh from the text, which would be darn near hopeless. Although you can certainly learn to appreciate the elegant style of Feynman, you may never learn to think about physics in quite the way that he did.

I think I’ve been very lucky, because I've been blessed with some people who were extraordinary and self-motivated. In some ways, all I really did was wind them up and let them go. If I were to take credit for anything, it would be that I established an environment where they could be wound up and let go. I ran a lab where getting wound up was an okay thing to do. And letting go was an okay thing to do. One of the things that I emphasized, for example, was to try to build up their communication skills. I devoted a lot of energy -- and this is something that I think a lot of physicists neglect altogether – into getting my students to speak and write well. This has had serious, positive impact, on their careers. I learned that from Max Delbrück. Max would hold weekly meetings for his group, and he would make everybody get up and give a talk. Maybe they wouldn't all speak the same week, but everybody in the group eventually gave a talk. This even included the technician who made the buffers and media, and the assistant who ran the dishwasher and autoclave. She would have to get up and deliver a talk about what's up with the autoclave – and there’s more to this than meets the eye! And I would have to get up, too. I was just a student helper. Max would often interject after a few sentences and say, "That's not the way to say it. Here is how to say it." He would stop us dead in our tracks and offer a better explanation. Max didn't exactly win universal approval for this behavior. He was pretty infamous at Caltech, in fact, for getting up in the middle of seminars, or asking impatient (and some thought impertinent) questions. He didn't suffer fools. Some junior faculty member would be giving, for example, a tenure talk, and Max would always sit in the first two rows. Halfway through the lecture, if he didn't like what he was hearing, he would get up and say, "I don't believe a word of it." And he would leave the room. (both laugh) So this didn’t exactly endear him to some people.

But what Max did do -- to his credit -- was really teach you how to think about not merely what you’re saying, but how you're saying it. He taught you to consider how you would communicate to someone 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 interesting. Or important. And I think, insofar as I've been able to get any awards for my own teaching, it's because Max taught me to care about communication. Howard Berg, for his part, was a superb writer of scientific prose. I would send him a page of what I thought was careful writing, and it would come back with entire paragraphs crossed out. He'd say, "You don't need to say this, you don't need to say that." Brevity and pith were the two bywords that Howard Berg lived by. He had a way of conveying something comparatively complex, which, by the time he wrote it, seemed remarkably simple. Even if it wasn’t really. He didn't use a lot of jargon or sophisticated vocabulary. For example, you don't ever “elucidate” something, you just show it. He got red-penciled of a lot of the silly cliché’s that scientists tend to write with. He managed to write simply and straightforwardly, and I learned a lot from that. My writing style improved enormously with Howard, my speaking style improved enormously with Max. One of the things we always did in my own research group is that everybody had to get up and give practice talks. And more practice talks. We would be relentless in critiquing them. They would get in three sentences, and we'd stop them right there and say, you know, "That slide has the wrong font. On that slide, the graph is invisible. And what you said about it, well, that's not what you need to say. This is how you should say it." The ghost of Max!

Zierler:

Yeah, yeah.

Block:

This relentless attention to detail in communication worked out really well in quite a few instances. Perhaps the most famous story regarding that related to a talented postdoc in my group, Chip Asbury, who today is a professor at University of Washington, in Seattle: the same university where I went right after high school, to all these many years ago. Chip was finishing up his postdoctoral stint, where he’d done some elegant work on kinesin motors. I think mentioned earlier that under some conditions, kinesin molecules “limp,” that is, they consistently take more time for one of their two heads to step than the other, and this tells you that the two heads must alternate. Well, he’d been a grad student at the University of Washington before coming down to Stanford, and he was an avid sailor. His dream job would be to return to the UW, and he wanted no position more than that. As it happened, they conducted a faculty job search at the UW in biophysics, but his paper came out a bit late, and the job search had already been closed. But I got on the phone and I called the folks responsible for the search, and I said, "Look, I know you may have already made your selection, but if you haven't actually told that person yes or no just yet, then you should definitely at least hear my guy out. Hear him speak about this work, and you might change your minds. But even if you don't, it's very little ventured."

Anyhow, I convinced them to invite Chip up to Seattle immediately for a last-minute interview. Chip had just 72 hours get up there and give a talk that he was not quite prepared for. So, during the first 24 hours, we had him prepare some slides, and over the next day or so, we grilled him nonstop about his presentation. We made him change this slide and that, and rephrase this explanation and that. We really put him through the gauntlet! But the result was something elegant and well-polished. Chip went up to Seattle and, to his credit, just knocked it out of the park. Although they had been very close to calling up their original selection and awarding him the job, they instead gave it to Chip. Today he's a happy camper at the University of Washington. If you asked him today, he, too, would likely credit the experience of practice talks in our lab for his success in getting that first faculty job. Of course, all his success since that time falls on his shoulders. As I've spoken over the years to various past graduates of my lab, one of the things that they often mention is, "Oh, I remember all those the practice talks in the Block Lab. I remember how you raked us over the coals, on either how to illustrate something or to say something.” Or, they’ll recall, “I remember revising that manuscript endlessly, and how painful it seemed at the time, because you kept changing things. You would rewrite everything I said. But boy, did I learn well, and today, I think back to that every time something goes well. And I try to do the same for my own students.” (laughs)

Zierler:

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 modes 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?

Block:

Oh gosh. You know, for most of biophysics, and with the rare exceptions, things like relativity, gravity, and even quantum mechanics are scarcely applicable. There's a limited application of quantum mechanics, for example, to proteins that sense or transduce light, like chlorophyll and the antenna pigments. Or anything fluorescent, phosphorescent, or luminescent There's a limited application of gravity, for example, in plants or other organisms that can tell the difference between up and down, and our ability to sense motion. But by and large, most of biology is explained by Newtonian mechanics, and fairly straightforward physics. I think you can get an awful long way with 19th Century physics in modern biology. But 19th Century physics, of course, is a beautiful edifice. I’m thinking especially here about statistical mechanics and thermodynamics, which are directly relevant to a great deal of biophysics. And getting into more modern physics, non-equilibrium thermodynamics is relevant to biophysics. The intriguing aspect thing about all this, from my perspective, is that if we really want to understand something, then one way to describe “understanding” is to say that when you comprehend something on some level, you can somehow connect that understanding to an understanding at the next level of complexity, either going up or down. There are a great many levels of understanding, from particle physics all the way up to philosophy. We tend to 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 internal compartments and organelles. And we understand them in terms of macromolecules, like proteins and nucleic acids … and so forth. You can keep working your way down, of course: nucleic acids are made of atoms, and so on down the line. Real “understanding,” from one point of view, is simply a way to formulate some description that passes, in a continuous way, through these many different levels of description. Many physicists spend a lot of time worrying just about the lower levels. They don't seem to spend as much time worrying about how to connect things up to the next level. But some do! Condensed matter physicists worry about that a lot, I think. And by "lower level" I don't mean intellectually inferior: I mean, in some sense, smaller sizes and smaller realms of time and space. I see biophysics as really about trying to connect up the richness of life, as we experience it, to the complex interactions among the molecules that are most responsible for life. Those molecules include proteins, nucleic acids, carbohydrates, lipids and so on.

So, how do we wrap our heads around that? Those stories cannot be explored, in most cases, just by the biologists. They can't even be explored by biochemists. I think that they ultimately may need to be told by biophysicists. So what parts of physics do we use? Well, there's a whole branch of physics which is really about the science of measurement. Most experimental physicists use various tools of measurement to observe nature, ranging from giant radiotelescopes astronomers use all the way down to microscopes and below. One thing physicists are particularly adept at is making careful measurements, including how to do the statistics properly, how to perform the data analysis properly, how to handle errors properly, etc. You need to know when to believe your numbers, and when not to believe your numbers. These are the tricks of the trade for experimental physics, and these same tricks of the trade really help the biophysicist to get farther along, say, than a traditional biochemist or geneticist might otherwise. There are modern statistical and analytical approaches, for example, that are familiar mainly to computer scientists and applied mathematicians. They're being applied these days, like gangbusters, to handling large datasets containing biological information, in the area of bioinformatics. There's an example of a growing field that's got little to do with biophysics, but also one where increasing insights into topics like gene control are being supplied by a next generation of scientists: one who can develop computer algorithms and who understand statistical methods that allow them to extract information from gigabytes of DNA sequence information. These are examples of things that most traditionally-trained biologists would be incapable of doing. In the same way, there are things that a biophysicist can do with experimental data that a traditionally-trained biologist is equally incapable of doing.

A case in point: protein structures were first determined by folks who didn't start off as biologists, but mostly as physicists. The modern field of crystallography grew out of physics roots, and so did the other structural biology fields of NMR and cryo-electron microscopy. I’m thinking of the Braggs, father and son, and Bernal, Hodgkin, Kendrew, Perutz, Crick. So, in a similar vein -- and this is germane to your question -- the physics that most biophysicists use is by no means arcane or difficult physics. It doesn’t use gravitational tensors and it's not multidimensional string theory. While the physics is mostly straightforward, it is nonetheless being used with state-of-the-art instrumentation and state-of-the-art analysis techniques to get insights from a physical perspective about the molecules of life. One example, which I could cite immediately, involves statistical mechanics. Folks with a degree in physics have all taken stat mech. And one thing we recall from our stat mech classes is that any time you tackled a problem, you were told to solve it adiabatically, or quasi-statically, or reversibly, and all those words refer to the fact that when you start to consider things far away from equilibrium, it's very hard to write down the thermodynamics. Non-equilibrium thermodynamics is a challenging subject all on its own, with few solutions. However, in the late 1990s, Chris Jarzynski at the University of Maryland published Jarzynski's equation. He showed, amazingly, that you could derive the equilibrium free energy for a given reaction by measuring transitions in that reaction away from equilibrium. If you measured enough of them, and if you gave them appropriate weight, to form an exponentially weighted average, then this average of the work performed is equal to the exponential of delta-G, the equilibrium free energy. It’s a result you can write down in one line. It looks totally simple. On the surface, it looks like a freshman might be able to derive it on the back of an envelope. In actuality, it requires many, many pages of difficult work to derive, despite its disarming simplicity. Jarzynski's equation, and related non-equilibrium work since that time, have opened up an entire field of endeavor in biophysics, involving molecular folding of proteins or nucleic acids. When a long polymer, like a protein or a stretch of RNA, folds, biophysicists seek to know how much energy is associated with the folding. In single molecule experiments, when can grab both end of a polymer and pull it apart. This involves applying forces that are well away from equilibrium. Then, we watch it snap back together again. Again, that away from equilibrium, and there's no way we can do this operation quasi-statically, reversibly, or adiabatically. But Chris Jarzynski showed us that if we make enough of these measurements, and we make them accurately enough, we can actually derive the equilibrium free energy for folding.

Subsequent to his work, there have been a number of important Physical Review papers by folks like Gerhard Hummer at the NIH, and Olga Dudko at UCSD, who are among a small group of theoretical physicists working in a biophysical context. They’ve expanded our arsenal of mathematical tools for tackling these folding problems. And there have been a number of important experimental papers that have demonstrated the usefulness of Jarzynski's formalism; and a related formalism called the Crooks fluctuation theorem. We can apply these theories to the problems of protein folding, the problems of RNA folding, and the problems of DNA folding. To my mind, this represents a beautiful example of how new physics, from the 1990s, can be used to solve important problems in biology. So, the connection between these disciplines is still alive and well, even though it may not involve the kind of sexy mathematical physics you read about from string theorists. So, my two answers to your question, about what aspects of physics might be most applicable to biophysics, at least as I practice it, are that there's a lot of stat mech involved in what I do. That's number one. And number two is that it's not so much about the complexity of the physics, per se. It's about the complexity of the physicist! It's the sophistication of the techniques that we can bring to bear. It’s about the experimental methods we can invent, the data analysis techniques we master, and – I’m back to using this word again, it’s about the mindset we bring to the problem, that really makes biophysics a branch of physics.

Zierler:

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.

Block:

Thank you.

Zierler:

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?

Block:

Well, let me try to tackle the last bit first, which is that I think it's fine where it's going. I don't think it requires me to shepherd it. It's certainly not spinning off in the wrong direction, in my opinion, and I don't see any compelling need for me to get involved to help guide it into the correct future direction. Besides, I think anybody who tries to guide science like that is being a little bit foolhardy, because you know you can't just imagine where things are really going on a very long time scale, and you can never predict what next new, serendipitous discovery might not lead somewhere else. So, I think it's generally a bad idea to try to guide science off in some direction. I realize, though, that funding agencies try to do this all the time. (laughs) I have to say that when my fellow scientists generate five-year plans for some grant on where they wish to go with their research, it's only a tiny fraction of the time that they actually wind up going in the same direction as they wrote in their original proposal. Some of it might be accurate, and 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, and, I’d argue, a deeply under-appreciated 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, it’s something that fell into our laps as a result of our latest findings. And that's entirely appropriate. That's the scientific method! If we try to chart a path too far into the future, we do so at our own peril.

So, to return to the third part of the question, I don't feel a compelling need to guide science in any particular direction. And I think the field is doing just fine now, and will probably do just fine without me. Although, of course, I would much rather do it with me. But that's what it is. Now, in terms of the general field of biophysics, I think the field is in a good place right now. I sort of answered this earlier, but as evidence of that, the meeting on single molecule biophysics that I run every two years has blossomed. We have mailing lists of order of 1500 people who are interested in this meeting, and we can only accommodate around 100 participants in the auditorium at the Aspen Center for Physics. On top of that, two of my young colleagues, Nynke Dekker at TU Delft and David Rueda at Imperial College, London, have started a European version of the Aspen meetings, to be held in the alternate years. Professional societies now consider single molecule biophysics to be a bona fide research topic, and that didn't exist except, in my mind's eye, 15 or 20 years ago. The Biophysical Society gives out an award in single molecule biophysics. So, the field is in a healthy state, and I expect that will continue.

The first part of your question is, where is it going now? And I suspect it's probably going, more or less, in about same direction that I was headed with my research, but also ramified in other ways. Given that you can learn so much new stuff at the level of single biomolecules, then single “anything” suddenly becomes attractive. On the sequencing DNA side, there's now single cell genomics. Instead of sequencing DNA molecules pooled from some tissue, you can sequence just a single cell from the body. You can also score all the RNA molecules present in a cell, for single cell transcriptomics. Why would you want to do these things? Well, some cells are cancerous and have aberrant genomes, and you might want to learn about that. And most cells adjust the genes that they express in response to environmental cues, including assaults from diseases. It also it turns out that the cells of our immune system splice their own genomes to create antibodies, producing novel protein sequences that have never existed before in the history of our organism, and possibly in the history of our species. The mechanisms by which we make these are not well understood, and each cell is a little bit different. Folks are very excited now about working with just one cell. That means there's just one DNA molecule. There are 23 chromosomes, or 46 actually, because they're duplicated. So, in principle, every gene is present exactly twice, and the two copies are a little bit different because they were derived from two different parents. So, techniques are becoming so sensitive now that it's possible to contemplate all that. People are working hard in that direction, and it has the potential to revolutionize some aspects of medicine. 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 deeper questions in biology that I alluded to earlier was the subject of gene control. In fact, the ultimate expression of gene control is what biologists call developmental biology. How does an animal grow from an embryo into a complete organism? How does my growing nose know when to stop, and not go out like Pinocchio's? This all has to do with the fact that my cells all contain sophisticated instructions. If we really want to understand biology, then sequencing all the DNA is not going to be enough. Every cell in my body is acting differently. And we’re soon back to confronting nature versus nurture questions. Is it just the background of the cell, and the experience it had in the fetus, growing up? Or is there something like a clock that’s ticking in the cell, and changing its behavior as a function of time, so that it's predestined to do certain things? Of course, both of those things are true. But how do we understand developmental biology? It’s an entire field, and biologists have been working in it for many years. I suspect that single cell DNA sequencing, combined with single cell RNA transcriptomics, will have a lot to tell us about development. These are the kinds of things that have the potential to revolutionize our understanding of biology. At this point, it's almost become a cliché, but when single molecule biophysicists get up and deliver lectures, they often begin by making a case about why it's important to study single entities. Now, most 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 might be misled.

One analogy that I offer is that I show a slide with a map of the Western hemisphere, and I show the route that a ship that would sail from, for example, New York to San Francisco. Now, if the ship is small enough, it goes down into the Caribbean, crosses through the Panama Canal, and comes back up the Pacific side. If the ship is too big, however, it's got to go down around Cape Horn at the tip of South America. So, I ask the audience to consider the average path taken by all ships traveling between New York and San Francisco. Well, that average path might take you through the center of the Amazon jungle, pass over the Andes, and come down through the Atacama Desert -- the driest place on Earth -- before it finally reaches the waters of the Pacific and turns northward towards San Francisco. Obviously, no ship has ever taken the average path. So, if you can only measure averages, you might be inclined to reach a wrong conclusion. It pays to understand what the individual entities look like. And again, this represents the instinct of a physicist. Biochemists, to this day, still work with roughly Avogadro's number of molecules. And that's partly because they have to. Their techniques don't have the sensitivity, by and large, to get down to single molecules. it's only been in the last decade or two that measurement techniques have become so sensitive that we can even contemplate doing these kinds of things, like measuring the displacement of a single protein at the angstrom level. Or measuring the propertied of a single DNA molecule. Or measuring a mere handful of RNA transcripts, and so on. These are among the technologies that are being pursued by biophysicists. Another recent Nobel prize went to super resolution microscopy, pioneered by people with physics backgrounds; folks like Stefan Hell, Eric Betzig, W.E. Moerner. And Xiaowei Zhuang deserves a lot of the credit, too, for this development. Let’s not forget that before that, physicists were responsible for nearly all major developments in modern microscopy, including Ernst Abbe, who first gave us an understanding of resolution limits. And Nobel Prizes were awarded for the invention of the phase contrast microscope, the electron microscope, and the scanning tunneling microscope. And cryo-electron microscopy, too. I suppose you could say that all these microscopies are based on 19^th, or perhaps early 20^th-century, physics, But it's still physics, and there’s a whole lot of mileage left in “old” physics.

Zierler:

Well, Steven, I don't know.

Block:

I don't know about you, but I'm tired. (laughs)

Zierler:

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 Neils 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.

Block:

Well thank you, it's been an unalloyed pleasure speaking with you. You not only ask great questions, but I'm amazed at your ability to anticipate where things are going, because I sense a resonance.

Zierler:

Well, it's what I do for a living, so I try to be good at it. So--

Block:

Well you sure are. Anyway, no one has kept me talking this long except my wife Kathleen when we were first dating. (both laugh)

Zierler:

I'll take that as a compliment, and I'll end the recording here.