Erin Schuman, Research Leader in Cellular Mechanisms and Neural Circuits

As one of the world's preeminent neuroscience researchers, specializing in synaptic plasticity and neural circuitry, Erin Schuman has great insight into the origins of chemical biology and Caltech's role in its creation as a discrete and blossoming field. As she simply and elegantly puts it, chemical biology is a way of bringing chemistry to life, and Schuman has put this approach to powerful use in her fundamental exploration of brain function.

In the discussion below, Schuman reflects on her early interests in learning and memory as an undergraduate at USC and how she expanded this focus to studying the role of ion channels in harboring memory during graduate school at Princeton. For her postdoctoral experience at Stanford, Schuman describes honing her laboratory skills in studying thin samples of the hippocampus to study its circuitry and plasticity. As a faculty member at Caltech, which she refers to as an "absolute paradise" to do science, Schuman describes the formative role of her collaboration with (now) Provost Dave Tirrell and working at the intersection of chemistry and biology. Schuman describes the difficult decision to leave Caltech to join the Max Planck Institute for Brain Research, the cultural adjustments to life in Germany, the new research avenues afforded by a mid-career switch, and her efforts to encourage and elevate women in science.

Schuman is an Elected Member of the German National Academy of Sciences Leopoldina, Academia Europaea, and the National Academies of Science. She has won the Federation of European Biochemical Societies Award, the Rosenstiel Award, the Louis-Jeantet Prize for Medicine, the Society for Neuroscience, Salpeter Lifetime Achievement Award, and most recently, the Brain Prize, "for having made ground-breaking discoveries by showing how the synthesis of new proteins is triggered in different parts of the neuron."

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Tuesday, September 18, 2023. I am very happy to be here with Professor Erin Schuman. Erin, it's so nice to be with you. Thank you for joining me today.

ERIN SCHUMAN: Thank you, David. I'm happy to participate in this project.

ZIERLER: To start, please tell me your title and institutional affiliation.

SCHUMAN: Sure. I am a Director of the Department of Synaptic Plasticity at the Max Planck Institute for Brain Research in Frankfurt, Germany.

ZIERLER: Tell me a little bit about where the Max Planck Institute for Brain Research sits administratively within the constellation of all of the Max Plancks.

SCHUMAN: Our institute is one of 80 or so Max Planck Institutes, and it's in one of three sections of the Max Planck Society, the biomedical section. It's one of around five to six neuroscience-focused institutes. Actually, it's an institute that is historically one of the very first brain research institutes in the world. It's over 100 years old. It began as the Kaiser Wilhelm Institute for Brain Research more than 100 years ago in Berlin.

ZIERLER: A nomenclature question. Neuroscience, neurobiology, are these interchangeable for you, or are there meaningful distinctions there?

SCHUMAN: Well, neuroscience is probably the larger umbrella term, and a point of pride for all neuroscientists is that it is, by definition, an integrated science. It draws on, of course, biology and psychology, but also computation, and physics, and AI. Probably neuroscience is a better term to encompass the entire field. Although, neuroscience and neurobiology are used interchangeably. But we draw on the expertise of people who come from many different fields.

ZIERLER: Tell me about your lab. How many graduate students and postdocs do you generally have?

SCHUMAN: I have around five graduate students and nine postdocs right now, but I also have an amazing group of permanent people, technicians, and permanent staff who really are kind of the bedrock of the science that we do. They provide a lot of steady, in my case, cultured neuron material that allows us really to do the experiments we do without having–like, in the US, this model would be, you would have a technician in the lab who's in between their bachelor's and their PhD. They come in and take a year to get good at something, then leave a year later. Whereas in the Max Planck Society, we have career technicians- I call them "the divas", this group of amazingly talented women who provide us with the foundation we need to do our work and assist us with experiments.

ZIERLER: As director, what are some of your major administrative responsibilities?

SCHUMAN: Well, that depends. In all Max Planck Institutes, the directors rotate into an administrative role, which I have just rotated into, which is managing director. Which means that you basically are the director of the entire institute, so over all the labs. And when you're managing director, it means that you're signing the contract for every employee and dealing with a lot of administration. One nice thing and one not-so-nice thing about Max Planck Institutes is that they're very independent administratively. We have the mothership in Munich, which is where the general administration is, and they provide us with a list of rules and guidelines that we have to comply with because we get our funding from the federal government, largely. But the administration and the daily running of the institute is left up to the local hands. When you're managing director, a lot of that falls on your plate. But besides that, when you're not managing director, you're just responsible for running your lab. But you do so in a way, if I compare to Caltech, it's more work because you have to manage your budget, and you also have to participate in the administration of the whole institute in a way that you don't if you're just a faculty member.

The Function of Brain Cells

ZIERLER: Tell me about some of the major research initiatives in your lab. What are the big questions your group is looking at?

SCHUMAN: From the earliest days when I started my lab at Caltech, we became very interested in how individual brain cells called neurons function. And we were particularly interested in how synapses work, so the connections between neurons. And because we know that in all cells, proteins drive the function of cells–this is also the case in synapses–the constellation of proteins that is present at synapses determines how that synapse works, how strong or weak it is. And I don't know if you can create a mental image of a brain cell, but you have little round sphere, like all cells have, but in fact, most of the volume of a brain cell is not in that sphere but rather in the processes, which are the dendrites and axons that send and receive information. It's within that halo, or you can think of it like the arbor of a tree, that synapses are made. Most of the protein that the cell produces is used out in those processes. Early on, we became really intrigued by how an individual brain cell can make the protein that it needs and get the protein to the right place at the right time.

The dogma when we entered the field was that all of the protein was made by machines that were present in the sphere in the cell body, and therefore, that's a huge demand that, in fact, probably could not be met if the entire sphere were filled with those machines, which are the ribosomes, but also would present a trafficking nightmare. If you take that sphere and then have to send proteins out to 10,000 different synapses at just the right copy number, it's an addressing system that is impossible to conceive of. We discovered that a lot of the protein is actually made locally. The machines are distributed–and not only are the machines distributed, but the template that's used to synthesize the protein, which is the messenger RNA, is also distributed. We've spent the last 30 years working on trying to understand the machines, the messages, and how the dynamics work out in terms of when a synapse is stimulated, what proteins might be made, what mRNAs might be moved there, all of those kinds of questions.

ZIERLER: I wonder if you can give me sort of a visual tour of the instrumentation in your lab. What do your group members work with?

SCHUMAN: First, as I mentioned, we work with neurons. And we either take the neurons from young animals (usually mice or rats) and culture them, where we have a lot of control, or we use neurons from genetically modified animals. The methods that we use are primarily modern molecular methods, like sequencing methods, and also a lot of imaging methods, and biochemistry. We want to understand the omics, so we want to understand the mRNAs. For that, we use RNA sequencing. We want to understand the proteins, so for that, we need proteomics. We use a lot of mass spectrometry. In those experiments, typically–although this is changing–you take the tissue out of its spatial context and analyze it. In order to take that information and put it back at an individual synapse, we need to do imaging, so we do a lot of imaging to visualize newly synthesized proteins or messenger RNA species in the processes.

ZIERLER: Does your lab work with human subjects at all?

SCHUMAN: Actually, we used to. When my lab was at Caltech, there was a neurosurgeon locally, at Huntington Hospital, doing a particular kind of neurosurgery that's amenable to recording. This is on a very different topic, though. My background is in psychology and learning and memory, so at the time, we saw an opportunity to look at how brain cells were changing their activity when humans were doing a learning and memory task. That was a period of time where via that collaboration with the neurosurgeon, whose name was Adam Mamelak, we did some experiments in humans. These types of experiments are continued at Caltech by faculty member Ueli Rutishauser- who was my grad student. But as a matter of course, the kind of cellular and molecular work we do now, we currently don't do any work with human tissue.

ZIERLER: Is that to say that your lab is more oriented towards fundamental research, that there's not necessarily a translational component to it?

SCHUMAN: I think that would be fair to say. I would say that what we do is foundational. First of all, at the level of a single neuron, one could make the argument that a rat neuron that we look at is very similar to what a human neuron looks like. And that's not just on visual inspection, but also in terms of the molecular components, they're quite similar and much easier to use. If we were to use human neurons now, the preparation that we would have to use would be probably induced human pluripotent stem cells. We would have to take a stem cells from a human patient, turn them into neurons, help them grow, and then study them. And those cells have problems of their own that need to be solved probably before they would become what I would view the cells we use, like a workhorse. The primary neurons we use are very robust, they don't vary a lot from week to week, so that we don't have this underlying baseline variability that makes it difficult to interpret the effects of our experiments. But I would say that the opportunities arise all the time to study human tissue and disease, and I have usually declined those opportunities, simply because I don't want to dabble in something. [Laugh] I only want to do things that I can do very well, and deeply, and thoroughly. It's always on my mind, and if at some point in the future, a situation may arise where I feel that we can go deeply into something, my answer might be different.

ZIERLER: Is there a theoretical component to your research, or is your lab basically an experimental operation?

SCHUMAN: My lab is an experimental operation, but the problem, as I may not have very well described it, is one amenable to theory. Part of our pursuit of the numbers and identification of molecules was to understand the playing field. Because we have a very good idea of what the morphological landscape of a single neuron looks like. If we could insert on that map of a neuron every single molecule, its copy number, if we knew the translation rate of this messenger RNA and how many copies of protein it generated, you could have all of the information you need to come up with a very good model. And indeed, we have collaborated with a great computational neuroscientist, Tatjana Tchumatchenko, to come up with what I would consider somewhat nascent versions of a big model that could be made at the end. But it's not something that I do on my own, it would always be in collaboration with someone.

ZIERLER: A topic that everyone is thinking about these days, machine learning and AI. Have you embraced these technologies, either as a research tool or just as a way to help you sift through enormous amounts of data?

SCHUMAN: Yeah, one clear application of that is in the analysis of some of the imaging data that we get. We are using cryoelectron tomography to look at the protein synthesis machines in neurons. And in cryo EM, you, of course, acquire a dataset. And then, you have a template of whatever you're looking for, in our case, a ribosome, and algorithms are used to match that template to existing structures in the images that you acquire and to understand the number of different structural states that machine could be in. The ribosome, with its two sub-units, twisting or ratcheting during protein synthesis, and the presence or absence of different RNA molecules or accessory proteins on the ribosomes as well as the detection of neighboring organelles can all use machine learning and AI methods in the analysis pipeline.

ZIERLER: Let's turn now to the topic that brings us together today. That is, my question about the development of chemical biology at Caltech. First, just a historical question. When did you first encounter the term chemical biology? Where were you, what were you doing at the time?

SCHUMAN: I cannot answer that question, but I can tell you that when we started doing chemical biology, I did not label it as chemical biology. Because I'm not a chemical biologist, that wasn't my frame of mind. And only later, I came to realize, "Oh, yeah, that stuff we're doing would be considered chemical biology."

Proteins at the Heart of Chemical Biology

ZIERLER: Let me refine the question. When you look back retroactively and say, "I guess what we were doing is chemical biology," what were you doing, and why would you define it that way?

SCHUMAN: I already told you about our interest in proteins. And in particular, we're interested in proteins that are being synthesized. It's all about the new proteins that are being made. For me, it's very poignant to look back on this because we made our initial discoveries in this field using a method that you would never use if you wanted to discover newly synthesized proteins and their role in brain function. We were using electrophysiology, so we were sticking electrodes into brain slices, and we discovered a form of plasticity, so a strengthening of the synaptic connections, and discovered that those connections needed newly synthesized proteins immediately in order to be strengthened. Because of the timing of the experiments that we did and the position of the synapses we were recording from, we came to the conclusion that those proteins had to be made close by.

Then, the question becomes, "What are these proteins?" And the methods at the time were radioactivity. In order to understand proteins, the handle that you would typically use is an amino acid. If you wanted to identify something as new versus old, you would change an amino acid, and you would change it at a particular time that would define the cohort of the newly made proteins. But that was done with radioactivity, so radio-labeled amino acids were dosed into tissue. Then, you would have a method where you would visualize by reacting those amino acids on film, you would be able to see the signal of the nascent protein. But you couldn't really imagine a method for identifying a protein, for example, with mass spec. Then, it was absolutely magic, I would say–there was a postdoc in my lab, Daniella Dietrich, who had a background in chemistry. Her fiance' was working in Frances Arnold's lab as a postdoc, so she was hanging out with the chemists.

And I guess she must've bumped into someone at a happy hour from Dave Tirrell's lab and discovered that Dave was working on a system that would make the use of radioactivity obsolete, which was the method that we later called bio-orthogonal non-canonical amino acid tagging (or BONCAT). Dave was working on functionalizing amino acids, not with radioactivity, but with chemical tags, so replacing the radioactive component in the amino acid with a tag or a molecular handle that could be used to mark that protein. And they had shown that when they introduced that amino acid to cells, they could fool the cellular machinery and get the cell's own tRNA synthetase to charge that amino acid onto a particular tRNA, and then further, that during protein synthesis, that tRNA harboring the artificial amino acid would be delivered to the ribosome and the noncanonical amino acid would then be incorporated into the newly synthesized protein.

We teamed up with Dave and started doing experiments in mammalian cells, and Dani showed that she could apply this artificial amino acid outside of the living cell and that it could label new proteins inside the cell. Then, we started doing mass spectrometry. We showed that we could, in the early days, use what we call an affinity tag to fish out the newly synthesized proteins, and then to submit them to analysis by mass spectrometry. In the very first paper, we identified 200 proteins. And now, we routinely identify 5,000. [Laugh] But it was super exciting and magical, really, when I think back on it, that we met up with Dave. And actually, that's one of the things I have always appreciated about Caltech, the smallness of the place really lends itself to this kind of interaction. A high concentration of smart people that occupy a relatively small landscape. If I were in a really big department at a medical school, I would never look outside of my own little world. I might explore a little, but it would be very unlikely that I would know what's going on in chemistry or even what my other colleagues in biology are doing because I would probably be in a neuroscience department. I really valued the smallness of Caltech as instrumental for the collaboration that I had with Dave. It would never have happened elsewhere.

ZIERLER: It's built on a happenstance interaction just because it's small.

SCHUMAN: Yeah, but also it was so small that it didn't seem like a big deal to start talking to someone in chemistry, and in fact, it's something that I've taken with my and kind of created artificially here. Here in Frankfurt, my institute is a brain research institute, but across the street is a university. When I got here, I immediately started looking up the chemists. Like, "Who can I chat with? Who are the chemists here who would be fun to talk to and think about things with?" But if I hadn't had the experience at Caltech, I would never have done that. I've just become sort of chemistry-bold as a result of my Caltech days and having the lucky chance to collaborate with Dave.

ZIERLER: To go back to a wonderful phrase you used, when you say you would never use these methods, are you saying that from the perspective of a biologist doing chemistry, or are you saying for your chemistry colleagues asking biological questions?

SCHUMAN: I think I mean the former. First of all, the physiology led us to this discovery. It wasn't like we were looking for it. It was a surprise discovery for us. We were just studying plasticity, and that was a perfectly reasonable preparation to use to start out with. But if you look at what the lab has built based on that very first observation, you would never guess that the kinds of experiments we do now (where we try to understand all mRNAs and proteins in the neuron) were based on a very simple electrophysiological recording, with really low-information content. We were recording extracellularly from hundreds of synapses, a technique that's not used that much anymore. It's just not the way you would've designed the experiment to make such a discovery or to launch this research that we've been working on all these years. And it's also, I think, a very good example of how you have to build technology to answer the question. Because also, at the time, there were really no methods for identifying or visualizing proteins with the kind of resolution we wanted.

ZIERLER: To stay on the topic of when chemical biology became a distinct field, now you know it's its own thing, you're looking at it retroactively, and you're saying, "We were doing chemical biology." When did you realize there was this field called chemical biology, and you were doing it without necessarily knowing you were a member of the club?

SCHUMAN: We were of course aware of Caltech's history of bringing chemistry and biology together – and closing the divide between them. We were also aware of a smaller world of people – the chemistry that was involved in the work that we did with Dave is a chemistry you'll certainly feature, which is called click chemistry. We were focused a lot on other methods that other people who were using click chemistry, like Carolyn Bertozzi, Dave's collaborator, and another group in San Diego. But it's not as if when we started doing these experiments, I was like, "I'm stepping my feet into this field, and I want to understand this whole field." I was still very much, and probably still am, really focused on, "What can I use? What do I need?" Everything we've done, even when we've developed technology, like the platforms we've developed with Dave, has always been very intentional.

You will find people, who I respect tremendously, and a lot of them at Caltech, who are technology-driven. "What is possible? What if? Can we do this? Can we make that better? Can we see this?" But for me, it's always been driven by something I want to know. But also, I have enjoyed the imagination aspect of, "What if we could do this?" And that's another thing I've really appreciated about working with chemists, is that I am admittedly incredibly naive about what's possible, and I think some of the people I've had the most fun with have been willing to just–if I say, "Can we make a sensor that turns this color when it's bound, and then is quenched and changes another color?" they'll be like, "Yeah, let's see." Go back to the drawing board. I think the combination of being unhindered by reality and teaming up with smart people who have a sense of adventure and a lot of know-how about the chemistry can be really powerful.

Foundations in Learning and Memory

ZIERLER: Let's do some personal history now to embed this narrative within your own educational trajectory. As an undergraduate, were you always interested in neuroscience, understanding how the brain works? Or that really developed in graduate school for you?

SCHUMAN: As an undergrad, I was interested in learning and memory. I was a psychology student at USC. And as an undergrad, I studied humans. I did a twin study, comparing mono- and dizygotic twins, looking at genetic and environmental contributions to learning and memory ability. That experience was enough to turn me off of human research for a long time. [Laugh] It was 7- to 12-year-old twins. I was driving my VW Bug to the Irvine School District, where I was able to get access to twins via letters I wrote to the Principals of Irvine schools. That turned me to thinking about animal systems to study, and I made the choice to work with a very simple animal system, an invertebrate, a mollusk that showed Pavlovian-style conditioning, and for which you could access the brain and define electrophysiologically the changes in the brain cells that are associated with learning. And from there, I just have basically been on a journey where I've become increasingly more molecular and focused over the years. The smaller and smaller substrates for specifying and changing synapses- like the individual ribosomes we study now and all of the work that I've already described. In the same vein that I stated that the experiment that started this whole endeavor wasn't the perfect experiment, I could say that my educational training for the things I want to do now wasn't optimal. Nevertheless, I do see advantages because I do have a big-picture view, and I understand the laws of learning and animal behavior. It always keeps me grounded a bit. [Laugh]

ZIERLER: Tell me about your decision to go to Princeton for graduate school. What was attractive about the neuroscience program there?

SCHUMAN: It's kind of funny: I joke about this with some of the faculty who were at Princeton when I applied, but then left when I showed up for graduate school. It was in the day before web pages, and so when I got the glossy folder advertising the neuroscience program at Princeton, there were people like Mark Konishi and Martha Constantine-Paton who were there. Mark then moved to Caltech, and Martha moved to Yale. When I got there, there wasn't the neuroscience community I was looking for, but I had already committed to work with my PhD advisor. It was kind of an apprenticeship-style program without rotations, so I was very attracted by the experimental system and the questions, and that's what really prompted me to move there.

ZIERLER: Tell me about developing your PhD thesis research.

SCHUMAN: Well, that was an unpleasant experience. My PhD advisor did not get tenure at Princeton and was universally disliked by everybody there. He didn't get tenure, I moved to Indiana University with him to finish up my experiments, and then when my relationship with him really degenerated and I had completed enough experiments for my PhD, I moved back to Princeton, and I told the department chair before I left Indiana, "I have to get out of here." And I was also advised by other faculty mentors to leave. I finished writing my thesis at Princeton and did some experiments with another faculty member, Greg Clark, as a very short postdoc before I went to Stanford.

ZIERLER: What are some lessons learned in navigating that difficult situation for you?

SCHUMAN: If I'm honest, it was really a battle between my PhD advisor and me, and I could see that he really wanted to get me to quit. It was a personal battle. I decided that he wasn't going to win the battle. I was also super fortunate that in the summer that the lab (which was just me at that point), was moving, I took one of the courses at the Woods Hole Marine Biological labs, the Neural Systems and Behavior course, and there, I actually met a lot of fabulous faculty like Tom Carew, Russ Fernald, and Darcy Kelly. I was there the whole summer, and they were the ones who really supported me through this transition and actually advised me, "You should leave Indiana," and supported me also in my search for a postdoc. They recognized that I had a lot of potential during that summer, and then helped me, wrote letters, and have continued to support me, actually. They were really life-savers. I think what I would often say to people when I talk about this, students and postdocs, is–and this would never happen today–to ally yourself with people who think highly of you, are supportive, all these things. But this kind of situation would hopelly never happen now. At that time, the were no thesis advisory committees, nobody at Princeton really monitored how I was doing or what my fate was going to be. I really was someone who could've just fallen between the cracks. But my toughness, I think, was what helped me to persevere in that situation.

ZIERLER: As a woman graduate student, do you think that was a factor in you not having the support that you might have otherwise gotten?

SCHUMAN: No, I don't think so, actually. I didn't know it at the time, but my joining the lab of someone who was really not a well-liked person, no one really bothered to engage with me so much. I think that probably was a bigger factor. A lot of women, we always kind of recount, "When in your career did you first notice gender issues?" And for me, it actually was when I first came to Caltech. It wasn't before that. I wouldn't have put my finger on a gender thing during my PhD or with my postdoc at all. My postdoc was great. It was only when I came to Caltech that I felt really in a minority, I would say.

Thesis Focus on Ion Channels

ZIERLER: What were some of your conclusions of your PhD?

SCHUMAN: I think the story that emerged from my PhD was very cool. We were studying brain cells in this animal that were harboring the memory, and I was studying, within these cells, the ion channels and currents that change the responsiveness of the cells. We discovered the mechanism by which a change in ion channel activity can be the basis for long-term memory. Ion currents can change because of differences in the abundance or nature of the channel proteins inserted. Another common way to change the function of a protein is phosphorylation; adding a phosphate group to the protein changes its structure, which changes its function. But phosphorylation is typically thought to be a signaling mechanism that operates over a scale of minutes: 5 to 10 minutes, maybe 30 minutes. But what my work showed was that there was a very long-lasting phosphorylation event of these ion channels, over 24 hours, that was required for this long-term memory. A kinase is the protein that adds the phosphate group to the substrate. We showed the persistent activity of a kinase can underlie memory and it was one of very few examples of really understanding how you could change information at synapses for a day or two days at a molecular level.

ZIERLER: Tell me about going to Stanford for your postdoc. What were your motivations there?

SCHUMAN: At the time, my major motivation was wanting to learn a particular preparation or approach. When I started graduate school, the way to understand learning and memory was to use these very simple systems, like the system I used or the one that Eric Kandel popularized, Aplysia. Marine mollusks, simple invertebrates. But during my PhD, people started being able to take brains from mammals and make brain slices that they could keep alive, and within those brain slices were little micro-circuits that could be studied. And a very popular preparation was to take the hippocampus, which is a brain area important for learning and memory, and slice it, and then study the circuit and plasticity. You could study a model of learning and memory just in that circuit. I wanted to learn that preparation, and I had a list of many labs. I got offers at all of the labs that I applied to, and it was one of my mentors actually from Woods Hole, Tom Carew, who strongly advised me to go work with Dan Madison, who was just starting his lab, but was also known to be a very nice guy and likely be a good mentor. Coming off of my negative graduate experience, it wouldn't have been good to choose a tough lab, I would say.

ZIERLER: This was a new research direction for Madison at the time you joined?

SCHUMAN: No, he had trained in this preparation. When I got there, I only knew I was going to start doing recordings. And I actually didn't know exactly what I was going to do. I spent a lot of time reading and coming up with ideas for projects that later turned out to be really great. But Dan basically taught me the technique, and then served as a really good colleague during the process of all the experiments we did together.

From Stanford to Caltech

ZIERLER: What aspects of the postdoc were brand new, and where were you building on what you had done as a graduate student?

SCHUMAN: I was trained as an electrophysiologist, so I was already very competent. I could get two micro-electrodes into a 10-micron cell and do very sophisticated voltage-clamp recordings. I needed to learn this new preparation, and my self-esteem had taken a major beating. I think the fact that I was very good at these experiments was very helpful, and also that things just started working right away. We had some good ideas that we tested, and I had two really beautiful papers. I guess I would say in retrospect that I exhibited some resilience, in a way, because I could've had a very long-lasting downtime from the PhD, but I think it was just such a great environment. It was a brand-new department at Stanford, there was a lot of energy, the postdocs all hung out together, we all worked our asses off.

When I look back, even though I've loved having my own lab and seeing my talented people really succeed and make exciting discoveries, I personally miss the kind of hands-on aspect of science. I think that's what got me into it. I very much like working with my hands, and physiology is the fine art of experimental science, in a way. There's a beauty to this execution of things with your hands, such as getting two electrodes into the same cell. There's a mastery associated with it that I find super rewarding. Later in my career, sabbaticals and other things, I've done other experiments that I just find the process super rewarding. But of course, that's not what I do every day any more as a lab head. In psychology, you would call these lab head joys secondary reinforcers because I'm not the primary recipient of the dopamine squirt from doing the experiments, but I do get immense pleasure from seeing our ideas develop and work with the people in the lab, but its not quite the same.

ZIERLER: Do you have a sense of the broader trend lines that compelled Stanford to create this new program in molecular and cellular physiology?

SCHUMAN: I do not at all, actually. I don't know what was behind that. The department was headed by Dick Tsien at the time. It's still a great department. I was just there last month.

ZIERLER: But was the idea that this was sort of a new field, that you were combining molecular physiology with cellular physiology?

SCHUMAN: Dick came from Yale. He was recruited from Yale to start this. It was a constellation of people who had mastery in the study of ion channels and people who were interested in synapses and plasticity with a little bit of cell biology thrown in. To be honest, that would be a sweet spot for me right now. I would love to have those kind of people as colleagues again. If I had to be in a small department, it would be that kind of department. But I think at the time, there were a few little hot topics that were merged in this department. One is the study of what we call long-term potentiation, which is what I was studying with Dan and what Dick was studying. There were some people who were amazing biophysicists, Rick Aldrich and Bill Zagotta studying potassium channels. Then, there were Richard Scheller and Tom Schwarz really figuring out mechanisms of secretion and neurotransmitter release. There was Stephen Smith, who was really pioneering imaging methods. It was really a fabulous mix of people. And also, they attracted really fun and interesting people as well.

ZIERLER: I'm curious, just being at Stanford in the early 1990s, was startup culture already happening? Were people talking about biotechnology?

SCHUMAN: Just a tiny bit. By the time I left Stanford, some of the faculty members were maybe either founders or on boards of startups. But it was really, really nascent, not at all what it later became.

ZIERLER: As prelude to you joining the faculty at Caltech, I'm just curious if Caltech biology, biochemistry, or chemical biology loomed large in your world at all, if you were aware of Peter Dervan, for example.

SCHUMAN: Not at all. I think it's very interesting to contrast perhaps people of my generation–really enjoying doing my postdoc, but also thinking about what I wanted to do next. But I wasn't thinking of even getting a job, I was thinking of doing another postdoc because I was having so much fun and thinking about who I wanted to work with. Then, actually, Dan had gone to Caltech to give a seminar and had talked about my work, and they asked him to ask me to apply for a Biology Assistant Professor position. And I was not thinking of jobs. I knew little of Caltech, although I was born in San Gabriel. The Biology faculty asked me to apply for this job. I knew this job search had been going on for a long time, but later, when I became a Pew Scholar, I found out that almost my entire cohort of Pew Scholars all over the US had applied and interviewed for this job before I got it. I think that the faculty was so rancorous and had so many special interests that they couldn't decide or come together and converge on anyone to offer the job to. I actually think that there wasn't a lot of convergence for me either. In fact, I know my husband preferred the other candidate. [Laugh] But they just were worn out. It was like, "We're tired, nobody wants to go through this search anymore. Let's just take Schuman."

ZIERLER: This is obviously a question for Dan, but do you have a sense in conversations with him what he emphasized about your research that turned heads during his visit to Caltech?

SCHUMAN: First, there was one aspect, which was, we showed that a gas, nitric oxide, was serving as a messenger in the brain. There were exciting ideas about this because the enzyme that generates this gas had been identified in the brain. People were really wondering what it could do. What we showed was that, as you might expect from a gas rather than a conventional neurotransmitter in the brain, which is released from one cell and then crosses a very small gap to interact with specialized receptors that are right there, that a gas generates a sort of cloud. One would expect that anything under that cloud would be influenced. And that's basically what my experiments showed. I showed that plasticity generated at one set of synapses could spread via the actions of this gas. And in order to do that, again, the technical aspect comes in, that I had to record simultaneously from cells that were all either very close or very far apart to discover the spatial rules by which this spreading occurred.

The recordings then were all what we would call blind, which means you can't see the neuronal cell bodies you are trying to record from. You can look through the dissecting scope and roughly see where the electrodes enter the tissue, but you can't see anything else. And then, retrospectively, because we were filling the cells during the recordings, we could see how close they were. And sometimes my two electrodes had impaled neighboring cells, so without actually seeing the cells, we had recorded from neurons that were point to point, 10 microns apart. It was exhilirating. It was very "macho" science, in a way, getting those recordings. And Dan was super proud of that, and I think he did a very good job of drum-rolling the difficulty of the experiments and showing two adjacent cells that had been blindly impaled by me. We showed that when the neurons were close together, changing the synapses in one neuron could lead to synaptic changes in the other- by the cloud-like influence of the gas nitric oxide.

ZIERLER: When you joined, was it already BBE, the Division of Biology and Biological Engineering?

SCHUMAN: No, it was just biology. That happened after we left.

ZIERLER: Tell me about starting up your own lab as an assistant professor and how Caltech supported you.

SCHUMAN: Well, the Division supported me with very nice lab space and a good startup package. Again, this was before the word mentor became a verb, mentoring. In the beginning I missed the camaraderie and the fun that I had as a postdoc, because I was really just stuck in my space, setting up my lab, screwing amplifiers into racks. It was rather miserable, to be honest. If someone was starting up at the same time as me in my building, we would've had a natural liaison or be buddies. Ray Deshaies was setting up his lab in Kerckhoff, and he arrived, like, six months after me. We didn't really hang out much . Knowing what I know now, I would've made a greater effort to hang out more with Ray. But there weren't a lot of junior faculty close by, so it wasn't a lot of fun at the beginning.

ZIERLER: As you were mentioning earlier, thinking about things in gendered terms kind of dawned on you at Caltech. Can you expand on what you mean by that?

SCHUMAN: At multiple points. One thing was, there were some really great people. Some of the sort of older emeritus people, like Ray Owen, the loveliest person, he would take me for lunch sometimes. I was very close with Norman Davidson too. He and I collaborated. Norman also was really great. We would go for breakfast sometimes, and Norman would invite me to go to movies with this group of faculty. That was fun. But I remember distinctly that it was the first time I had encountered all kinds of different prejudice. Ray and I would be walking back from the Ath, and we'd bump into someone from physics, and Ray would say, "Oh, have you met our newest faculty member? This is Erin Schuman." And they would just kind of look at me like they didn't believe I could be a faculty member. Then, he would say, "She's a great teacher. She just got the teaching award." I remember one of them was like, "Oh, yeah, good at teaching. Mmm." The implication was that I couldn't also be a great scientist- despite many prominent Caltech examples that come to mind.

And then, during this whole period, we didn't have many women faculty in biology, and many of us were trying to confront the obstacles for recruitment and the obstacles forkeeping women in science. Pamela Bjorkman and I were executive officers in biology, and she and I really worked hard to change some of the policies. But I'll tell you something else that Gilles pointed out that actually comes with my tenure decision. The field I was in was a very male-dominated field, the one I started in when I was working at Caltech. And I mean in the larger context. All of the heavy hitters in the field were male, and there was a lot of, I would say, patrilineal relationships. Descending from key people was meaningful and gave you an advantage. And actually, one of my scientific grandfathers had harassed me when I was at a conference as a young postdoc. That patrilineal relationship did not help me at all. What I'm trying to say is that, in order to survive in that field, I had to be tough, right? I could not be a wilting lily. I had to be super tough, and stand my ground, and defend my science when it was challenged.

When I got tenure, I was invited to the chair's office, and the chair said, "Okay, well, you got tenure, that's great." He said, "Now, you can"–and I said, "What do you mean?" And he said, "You can back off a little bit." And I said, "What do you mean by that?" And he said, "Well, you don't need to be so tough or in-your-face anymore, Erin. I've heard that you're a little bit in-your-face, and you can back off." I was surprised and said, "Oh, okay." I walked back to my office very bewildered, and I called Gilles, and he said, "That's just sexist bullshit. [Laugh] He would never say that to Ray when he was getting tenure. He would be like, 'High-five. You're holding your ground.'"

I think it had to do with expectations. And that's something that we are all grappling with, what people deem is an acceptable scientific style for women versus men. And a lot of research shows that women have to thread the needle of not being too aggressive, being just nice enough, laughing just enough but not too much, because then you're not serious. But if you are too assertive, then you're labeled as aggressive. But all of these challenges contribute to your growth as an individual. And I think we did a lot of good things. It certainly gave me a lot of knowledge and experience to tackle some of the things that I've worked on here in Germany and in the Max Planck Society on gender equity.

Pursuing the Mechanisms of Plasticity

ZIERLER: From just starting up at Caltech and defining your research agenda to the process of going through tenure, how closely did you stay on track from your initial vision to what ultimately you were voted on for?

SCHUMAN: That's the other very interesting thing, if you see how we prep our postdocs who are going for the job market now and what's actually required for them, multiple chalk talks and several documents outline their future strategy–my job talk was, "I want to study mechanisms of plasticity. Oh, and by the way, I've started doing a little biochemistry. Here's a transparency of a gel that I just got that I am super proud of." There was no substance. There was nothing for them to say whether I deviated or not because it was so nebulous that it could've been anything. And that would never get someone a job today. My postdocs who go on the job market now have much better plans than I could ever articulate at that time.

I was just doing simple experiments, trying different things. I did have some plans, and those plans, the things that I started, actually were the seed that lead to our discoveries. Because the idea was, "Well, we know that during the development of the nervous system, there's a lot of remodeling of synaptic connections. Connections are being made and broken. Maybe some of those same molecular processes that govern that connection remodeling during development may be at play in the adult." And that experiment is the one that set us on our way. So in that sense, I would say I didn't deviate so much from my original plans- but those original experiments lead to a surprising discovery. During the time at Caltech, I definitely drilled down to understand protein synthesis in neurons, and then since I've left Caltech, I've really focused even more in the mainstream of my lab to understand protein handling, protein homeostasis in neurons, and as we say in the field, local translation. That's really the big thing that we focus on in the lab.

Fundamental Collaboration with Dave Tirrell

ZIERLER: We mentioned earlier in our conversation how your collaboration with Dave Tirrell started, but I wonder if you could just root it chronologically within your faculty time at Caltech, when that happened.

SCHUMAN: The very first experiments weren't in neurons, they were aimed at identifying the proteins that we would label with this non-canonical amino acid labeling. But with the click chemistry, the beauty of it is that you can click on anything you want. Once the label is incorporated into the protein, you could click on something that would allow you to pull the protein out of the cell, or you could click on a fluorescent molecule. And so, the next big step was to be able to visualize, then, the newly synthesized proteins within the cells. And within neurons, that was an absolute gold mine. Because the neuron is, perhaps, the most beautiful cell for looking at spatial domains because it's so complex, with all the dendrites and axons, we were able to show that the method could be used to now stimulate neurons and then see where the newly synthesized proteins are. That was another, I would say, quantal step.

The next quantal step was something that Dave had been working on for a while, which was to make the method one that you could use in some cells but not others. As originally conceived, the method made use of enzymes that were present in all cells. Once you add the amino acid, every single cell sees the amino acid and uses it to make protein. But as biologists and neuroscientists, we're interested in certain cell types. We want to be able to see cell A but not cell B. What Dave had been doing was working on a method where one could change both the amino acid and the enzyme that charges the amino acid onto the tRNA, and by changing the enzyme, you now have control. It's not the same enzyme that's present in all cells, it's a modified enzyme that you're going to put into your cells-of-interest using promoters that are cell-type specific.

We exploited that to develop platforms that can be used in all different model systems that are used in biology so that you can label the proteins in cell type A but not cell type B in mice, in zebrafish, in worms, and in flies. Basically, with the construct, you can do it in any organism, but we created this pipeline, and we used the method also to identify the proteins that were changing during plasticity, again, something you could never do before. The other nice thing, of course, is that other people use the method for other things. When I say plasticity, I'm thinking about synapses, but plasticity is when cancer cells invade a tissue or when a mutation happens in a particular gene or when the chemical environment changes in the ocean.

Then, you want to see how all the cells respond. The way you can do that is by looking at all of proteins made by the cell (the proteome), and this method allows you to do that. And by analyzing proteins, which are hard to analyze compared to RNA molecules, you're really looking at the molecules that do most everything in the cell. A popular experiment these days is to do RNA sequencing on every mutant gene in every Parkinson's model or Alzheimer's model, but the correlation between the messenger RNA and the protein on a protein-by-protein basis is around 0.4. RNA is not really the best molecule to look at if you want to really understand how a cell's function has changed. The protein is ideal, but it's harder to measure. But this method (BONCAT) that we developed with Dave really gives you access to it.

ZIERLER: I wonder if we could pull Frances Arnold a bit more into this narrative, the postdoc where there was this happenstance encounter. Was Frances already doing the kind of enabling research that just made the entire field explode? Was that already in train at that point?

SCHUMAN: It was. It hadn't quite exploded yet, but it was super exciting, and it was a parallel effort on campus. But I would say her work was more exploratory, a little bit more wild, wild West than what we were doing. But of course that certainly paid off hugely! Actually, I have a good early memory of Frances. Before we had published our first paper in my lab, this very foundational finding, she and I were at a dinner. It must've been when Everhart was president – so at a president's dinner. And she said, "What's going on? What'd you find?" After I told her, she escorted me around to all the little faculty clusters that were chit-chatting and said, "Do you guys know Erin? She has a very exciting find in her lab," and so on. It was lovely and very supportive.

ZIERLER: Now, with Frances Arnold, what she was able to do for evolution as a research tool, was that relevant at all for the collaboration between you and Dave Tirrell? Was there an evolutionary component for you?

SCHUMAN: I think you have to ask Dave that. My sense is that they knew what they were doing. It was much more targeted. It wasn't that when they were mutating the methionyl-tRNA synthetase that they made every possible mutation and saw which one worked. I have a feeling that it was much more targeted, that with knowledge of the enzyme, they could make some pretty good guesses about where they needed to mutate it.

ZIERLER: You mentioned Tom Everhart. Of course, when David Baltimore was named president, the historic nature of a biologist becoming a president of Caltech, how that registered for you and if that had any palpable impact on biology at Caltech.

SCHUMAN: I think it did, although we knew very well, and I think David even told us that whenever something like that happens, a president who has studied X joins a faculty, the faculty who studies X, at first glance, thinks, "This is going to be great for us," but then realizes, "He or she is not going to be able to play favorites in the short game. They definitely need to show that they're interested in the entire spectrum of disciplines that are represented at the university." I remember that when we first met with David, when he came around to all the faculties, he more or less told us, "Look, I'm going to need to really spread my attention throughout the Institute, and I'm not going to be able to give all the attention to you guys, where my heart is, really." I can't put my finger on anything tangible, but I think it led to an overall feeling that we were understood on campus. Because historically, biology had always been the kind of lowest-on-the-totem-pole science on the campus, I would argue. We definitely had this feeling that we were viewed as the inferior science on campus. With Baltimore coming in, I think as a division, we felt we could stand a little taller and were finally getting a little of the respect we deserved.

The Enabling Research Possibilities of HHMI

ZIERLER: Tell me about your longstanding affiliation with the Howard Hughes Medical Institute, how that started and what that enabled for you and your research.

SCHUMAN: I was appointed to HHMI in 1997, I think. And it was absolutely great, financial support, access to great colleagues and intellectual stimulation that was quite broad. I had that funding until I left, more or less, from 1997 to 2008 or 2009.

ZIERLER: Does that untether you, to some degree, from the constant proposal and review cycle from NSF or NIH?

SCHUMAN: Definitely, yes. It does. But I have to tell you, I'm even more untethered now. In the HHMI cycle, it was originally five years and then seven years of review. Every five to seven years, you were reviewed, and when I was there, it used to be that for your review you submitted your five best papers. I don't know if you've gotten a sense of the anxiety people at HHMI have over these reviews, but everybody talks about it. The other sort of really undercutting thing is that the HHMI people would tell you, "And don't think that if you have five Science, Cell, or Nature papers, that it's a shoo-in. It's not at all." And actually, I think that turned out to be true. It was like, you do everything you can, you publish great science at the highest possible level, and you still might not be renewed. That was certainly a level of anxiety that I felt and everybody else felt. But a lot of financial freedom also because the funding is about people. It's not for a project, like an NIH grant, where you have an idea, and you have to clearly delineate what the idea is. None of that, which I loved. That worked very well for me. But coming here, Max Planck is like HHMI, but more resources and no five- to seven-year clock. I was curious to see if it would feel any different at Max Planck and I do. I feel completely free to take risks, free to follow an idea that may not pan out. I think it's allowed me to do even better and riskier things than I did before.

ZIERLER: Is that to say that your research agenda took on a new trajectory, or were you able to more fully involve yourself in the things you were already doing?

SCHUMAN: I think we went deeper and more broad in our approaches. Instead of having to focus on one pathway, we can do a very deep analysis of whatever we're interested in in the broadest possible way, without having to worry about resources, being able to pay for the experiments. If it's a big idea, we also don't have to worry about failure. But actually, we haven't failed. [Laugh] I think it's been very liberating and perhaps we've been very lucky, but it's been the perfect formula, I think, for doing the best science that I can do, to just be given some money and free reign. And no one, even the advisory boards that come in, have said, "You should do more of this and less of that." It's just been support and encouragement, which has been great.

ZIERLER: Before we move on to your decision to leave Caltech and come to Max Planck, as a historian, I'm concentrating on this question of chemical biology at Caltech. While you were a faculty member there, did you have a sense that this was a field that Caltech was really an innovator in, or is this, again, sort of a more retroactive appreciation for how these things developed decades in the past?

SCHUMAN: It's hard to say. I would say a mix of both. I could certainly feel the contemporary energy while I was there of Frances's lab and Dave's lab. We definitely felt we were pushing the envelope, we felt like we were working on something new and exciting. And I would say I had the feeling it was a new field. But I didn't have the perspective, not being a chemist or being senior enough. Reflecting on these things takes time, both in the sense of years but also days. And I didn't have the liberty to really take stock of trends at that time. I was much more involved in the daily experiments and obsessed with what we were doing – so didn't have the time to stand back and take stock of the bigger field view. I didn't have the perspective that I've come to appreciate over the years, I would say.

ZIERLER: What about the intellectual origins, the trajectory deeper into Caltech history, what Linus Pauling was doing in chemistry, what George Beadle was doing in biology? Did you sense that trajectory at all? Or again, you're in the middle of it, and it's hard to see it in real-time?

SCHUMAN: I would say it's more the latter. I see it now in hindsight. But the question seems to be, "When you're part of history, are you aware that you're part of it?" And if I'm totally honest, I would have to say not as much as I do now with the benefit of time, being one of Dave's collaborators.

ZIERLER: That negative interaction you had with the division chair about chilling out a little bit, do you think that stayed with you? Was that sort of a push factor for you in thinking about the opportunity at Max Planck, the culture at Caltech?

SCHUMAN: No, not at all. Both me and my husband moved, and I really loved being at Caltech. For me, it still would be my preferred place to be. Those were all battles I was willing to fight, and that experience did not turn me away from Caltech at all. My overall impression is super positive. I think it's one of maybe two or three absolute paradise places to do science, for sure.

ZIERLER: As you grew in seniority and achievements–I'm not asking about other people's perceptions of you, but in the way that you narrated your own sense of not being a wilting lily, needing to be tough, did that sort of lessen for you as you grew more significant in the field? Or that never goes away?

SCHUMAN: I don't think so. I think it's partially my personality. I have not had this kind of fairy tale existence in science where I work with this Nobel laureate, and then that one. It's kind of a ragtag story of someone who was willing to work hard and had some good ideas. It's not a blessed story at all, as you can tell. I think my personal evolution has been that I am a person who will call out things. I'm still not a wilting lily. But in all the things that we tackle, in all of the issues besides just doing our science, whatever personal goals we have or things we want to better for society, everyone plays their role. And the quiet diplomat plays a role, and then the person who's willing to speak out and be somewhat brash also plays a role. I wish sometimes that I could be more diplomatic, but then I see that sometimes we need people to speak out, and then other people can reframe in a more polite way what I've said.

For example, in the Biomedical Sciences section of the Max Planck Society, when I came here the fraction of women directors was just 10%. And I was really aghast at the situation. I looked, for example, at the number of women who were HHMI investigators, and when I did the analysis, that was around 25%. I looked even in the division at Caltech of tenured faculty, and we were approaching 20%. I was coming into a situation where the fraction of women colleagues was half of what I had at Caltech. I worked really hard with a new colleague, Joe Howard, who was a Max Planck director in Dresden at the time, to write a white paper about this, showing the data from other places. We really pushed this forward and got many of our Max Planck colleagues on board, and now we have 25% women directors and we aim for more. We voted in new procedures and guidelines for committees and searches. I'm coming back to my brashness, which is to say that coming here to Germany, I think many people think that Americans are outspoken or more direct than Germans. For a while, I think my Max Planck colleagues thought I was just American, but now, I think they realize, "Oh, it's not that she's American, she's just outspoken." [Laugh] But for a while, I was able to hide behind my shield of American-ness.

The Move to Max Planck

ZIERLER: In reflecting on your decision to leave Caltech and come to Max Planck, were there specific research opportunities that were really compelling? Were there things you thought you'd be able to accomplish at the Max Planck that simply weren't possible at Caltech?

SCHUMAN: My work is easy to pitch for funding because it's very foundational, molecular, and has potential translational applications. My husband, Gilles Laurent, who was also on the Caltech Biology faculty, studies really interesting behaviors in model systems that are best suited to study those things. Like, he studies camouflage in cephalopods, and he studies sleep in dragons- animals that weren't thought to have REM sleep. He's very deep, thoughtful and insightful in the way that he approaches science. But this doesn't resonate with the way the NIH thinks about funding. In fact, a while back the NIH started cutting funding research in any model organism except the mouse- a disaster. There's now a trend that's sort of circling back. But the funding horizon for Gilles didn't look great. But he had been doing amazing work with the NIH funding he had.

When this opportunity arose to have the great Max Planck funding, it seemed very selfish for me, who had HHMI money my entire career, to deny him the opportunity to have this amazing funding. There was that. There was the fact that he's French, that we had been coming to Europe, we had our kids, and we thought it might be interesting to raise them in a different environment. Gilles was also joking, since our kids are all girls, that my goal was for them to become Pasadena Rose Princesses, which he knew would really push my buttons. Then, we had the opportunity to build a new institute. The Max Planck Institute that we're in now is not the one that was in Berlin, it's a building where we had a say in the design. We actually worked with the architects, and we knew very well from the various buildings we had been in at Caltech that space really matters, the physical space in which scientists and everyone works has an effect on their wellbeing, but also their creativity and their output.

In science, designing spaces where people are likely to interact and come together, we viewed as very important. What we didn't appreciate at the time is that the scientific way of interacting, running a place, bringing people together that we had a common vision for was also different from the typical German or Max Planck model. Here, our institute was called by a previous president "the American institute" because we have a lot of social activities, there are always people in the open spaces, there's a lot of noise. Some Max Planck Institutes you walk into, and it's absolutely quiet, you walk through an austere concrete hallway, and you make a left turn and a right turn, and there'll be one person working at a bench. We have a lot more buzz here. The idea of having a slightly higher packing density is also important for us.

ZIERLER: How was it wrapping up your lab at Caltech? Were you able to time it so that graduate students were not left in the lurch? Did you bring any with you?

SCHUMAN: I did bring some with me. Everyone was offered to come. I still think about this a lot because not as many people came as I had hoped. I had some beginning graduate students who decided not to come and then switched to other labs. I thought it was the ideal opportunity for someone to see Europe completely without all of the hassles. Because I had assured them that I had people in Germany who would help us find housing, that all of their transport and moving would be taken care of, but people were reluctant. I was surprised by that. It seemed to me that graduate school was the perfect way to experience a foreign country. Some of them already had interesting data so I thought there was potential for a positive experience. Not as many people came as I hoped, but I had two graduate students and two postdocs who came with me. I kept my Caltech lab running for a few people, so it worked out okay, I would say. And in Germany, we had people in place to help with the transition. A big move like this- it's better if you don't think too much about the hellish logistics in advance because you'll never do it, you just have to go for it.

ZIERLER: To the extent that you were coming to build something from the ground up, did that influence your research? Did your research move in new directions just by changing where you were working?

SCHUMAN: That's an interesting question. There were some new things that we started. We started the sequencing here, but I think we probably would've done it also at Caltech. I had the chance to optimize things. As things had evolved at Caltech, it was like, "Oh, I have this tiny, little space for something needs a lot of space." I was able to design space that was suited for the operation that I had, that was less than optimal at Caltech. But still, those are all little things. It helps a little bit, but you should be able to just get your stuff done in the space that you have, I think.

Missing Caltech

ZIERLER: What were some of the cultural adjustments, coming to Germany as a scientist?

SCHUMAN: That's been really tough, I would say. The thing I really loved about Caltech is how I really felt a sense of collegiality. I loved, in our Division of Biology, that I could talk to everybody, that I could have science discussions with Norman Davidson, Kai Zinn, Ray Deshaies, Mike Elowitz or Pamela Bjorkman and many, many other colleagues. I just thrive on that kind of interaction with people who aren't doing what I do. I find it very inspiring to hear their approaches and the way they think. I think it influences my thinking in intangible ways. I found that intellectual environment very stimulating and optimal for me, drawing on so many different aspects of biology and chemistry. Coming here to Germany, we have a three-director institute. I'm the most molecular person here. I don't have a molecular colleague. My approach has been more to rely on the people in my lab who are are fantastic as colleagues, and then through meetings and conferences. But I really miss the kind of day-to-day interactions that I found so valuable at Caltech. The culture here is also very different. Within the Max Planck Society, I would say, most of the institutes are rather insular. Even though collectively, we could organize as a large faculty, we would be 100 people, like one or two departments of Harvard Medical School, there's not really the instinct or the desire. This is not across the board, but I would say in general, Max Planck directors are attracted to these positions because they get money and space to do their own things, and they may not be so interested in collaborating or getting inspiration from colleagues. I've come to realize after being here for almost 15 years and making efforts to try to have more connections. Of course, there are exceptions which I am very grateful for.

ZIERLER: Do you know German?

SCHUMAN: I speak some German. We tried at the beginning to become fluent, but then we got completely overwhelmed with the building. I take that on me – I should have tried harder and carved out the time. I think my assimilation, if that is ever a goal, would have been greater if I had really mastered German.

Elevating Women in Science

ZIERLER: Your interest in promoting women success stories in science, either on the unofficial level or working within scientific societies, working in terms of how you present your work, did that sort of become more central to your focus when you moved to Germany, or were you involved with those things at Caltech at all?

SCHUMAN: I was involved with them. Pamela Bjorkman and I, as executive officers, worked on things like extension of the tenure clock for faculty with family, and the means by which those things are implemented, that they're automatic, rather than a pregnant professor going into the chairman's office to beg for a one-year extension. I was also on the faculty board at the time that we were doing an analysis similar to what MIT's analysis spearheaded by Nancy Hopkins and worked hard on the policies that were changed after that analysis. There was already definitely an interest, but I'd say when I came to Germany and saw the situation here, and also saw that we could do something, that the time was right to do something. I felt energized because I could see that we were making progress on gender issues, but I could also see that there were persistent impediments to progress.

Those things were worth fighting for. Here in Germany–it's probably true in a lot of countries–there's a mismatch between what are generally accepted as governmental recommendations for how to be family friendly and promote integration of women and men in the workplace that are completely at odds with other existing policies. They're internally inconsistent. Like, "We want to be family friendly, but you can't have a space in the Institute where you can bring kids or babies." These things clash. Because they're policies, and they're written down, you can then point out the inconsistencies and really push. We've really pushed the Max Planck Society to drive change in the government. Max Planck is such a powerful organization in Germany that it's really in a position to, I would say, push for social change rather than always be seeking compliance.

ZIERLER: Is that to say that Germany really has as much work to do culturally as the United States, or perhaps even more?

SCHUMAN: I would say so, yes. There are a lot of ingrained cultural issues having to do with women in Germany. Within families, there's the notion that if you have children, the woman should stay home. "Why would you have children if you're not going to take care of them 24/7?" They have a name for women who take their children to daycare and let other women care for them, "rabenmutter", like raven mother. They have a tax structure that favors women who only work part-time, so if you're a woman in a family, and you have children, if you work more than, 20 or so hours a week, you're penalized tax-wise. When families are making these calculations for what makes sense, financially, it always makes sense for the women not to go back to full-time work. And in Germany, if you have one child, and you worked full-time before, you only have, like, a 33% chance that you're going to go back to the workforce full-time. If you have two children, you only have a 15% chance that you're going to go back to work full-time. With numbers like that, you can see that there's a lot of work to do. And at many levels. Culturally, within the government. Those aren't things that I'm going to be able to change. [Laugh]

ZIERLER: With all of your administrative responsibilities, as your lab has grown and diversified, as you're interested in advocacy issues, how do you stay close to the science? Do you carve out special time every week? Do you really rely on graduate students and postdocs?

SCHUMAN: Yeah, I carve out time every day. [Laugh] For me, it's why I'm here. If I don't do that, then I should just pack it in, really. I meet with people all the time, whenever I'm in town. Today, I just had a three-hour meeting with one of my postdocs that was really interesting and exciting. It's just a matter of being organized and having priorites. And then, of course, in the off time, when you're not in the lab, you can be canvassing, reading increasingly abbreviated versions of things that have come out, not quite at the level of a tweet yet from all of my scientific content, but I fear I'll be there soon. [Laugh]

The Open Questions of Synaptic Plasticity

ZIERLER: Because you do have to carve out that time, it establishes, I would imagine, a hierarchy of what's either most important to you or most interesting to you. On that basis, just to bring our story up to the present, what's most interesting to you in the field right now? What are you most excited about in your own lab?

SCHUMAN: There are so many things, it's hard for me to pinpoint just one. One thing has to do with the spatial resolution of the things we want to understand. For us, the smallest unit we want to understand in terms of function is the individual synapse. Most of the experiments we've done thus far have been those where we can canvass or understand the mRNAs or proteins in a whole bunch of synapses that we can get from a certain brain area. But now, with advanced molecular methods for tagging synapses, we're on the cusp of being able to have almost single-synapse resolution of the information that we've been gathering. Besides just admittedly believing we should be able to understand an individual synapse, it's very important for us to understand the entire landscape, the state space that these synapses can occupy. And when we do experiments the old-school way, in bulk, we don't really understand that because it's all a big average.

Whereas now that we're getting glimpses of what individual synapses look like, we have an understanding of where the synapses can sit in this space, and then we can understand what happens when they change. During plasticity or during disease, are there new spaces that are created within this galaxy? Or are synapses just adding and deleting the same subset of molecules? Are the synapses moving to dwell more in a defined position in this space? Are new kinds of synapses being created, or are we changing the distribution of a known set of synapse types? And when I say synapse types, I'm talking about synapses that have a certain protein composition that would favor them responding them to a transmitter in a certain way or have a certain constellation of mRNAs.

And then, again, these questions are also important for understanding disease. What happens to the population of synapses in a diseased brain? Do they all get clustered over in one malfunctioning space? Are some states not occupied at all? Because there's an inclination right now to identify a cell type that is wrong in disease, but I think the emerging view is that it's really the entire state. Because these neurons, of course, don't work in isolation, they work in circuits, and cell types interact with one another. And so, in a disease state that comes on at birth, the whole system gets reorganized. And I think understanding the state space in the way that we're just about to be able to do will be really important for answering these questions.

Winning the Brain Prize

ZIERLER: Of course, we can't cover all of the ways you have been honored in your career, but I can't help but ask about the most recent one. This year, in 2023, you got the Brain Prize. Tell me about what the Brain Prize is and what you were being recognized for.

SCHUMAN: The Lundbeck Foundation would want you to know that it's the largest prize given in neuroscience in the world. [Laugh] And I was recognized, together with Christine Holt, my dear colleague, and Michael Greenberg, also my dear colleague–Christine is at Cambridge, UK and Mike is at Cambridge, Massachusetts–for work that we have done on gene expression. And in the case of Christine and me, the work I've been describing to you on local synthesis. Christine's work has focused on local protein synthesis in pre-synaptic nerve terminals that release neurotransmitter during development. And our work has been mostly in dendrites, the parts of the neuron that receives signals from other cells. But that's the body of work- the de-centralization of these machines and from the cell body- that has been recognized. Because, as I said at the very beginning, it was thought that all neuronal proteins were made in the cell body. It took a lot of work and a lot of careful experiments to convince a very skeptical field that protein synthesis occurs in neuronal processes. Mike Greenberg works on how activity changes the transcription of mRNAs, so it's another aspect of gene regulation.

ZIERLER: What was the breakthrough that allowed for this research to happen? What elements were experimental, what were theoretical, what was even perhaps a eureka moment?

SCHUMAN: I would say the eureka moment was the experiments I described. It was a 1996 paper, the experiments I did together with my very first graduate student, Hyejin Kang, at Caltech, that really got us started on this path. Because we discovered there's a form of plasticity that requires protein synthesis that's very far away from the cell bodies. And that was a puzzle, it was not something that had been integrated into the way people think about neurons. That was the first discovery. And then, for example, the methods we worked on with Dave were really instrumental because they gave us the tools to see and name the proteins that were being made. That was a key step.

Another key step was the ability to sequence the messenger RNAs and to figure out ways where we could, in these experiments, separate the dendrites and the axons from the cell body so we could, as a group, identify the population of mRNAs that are present here and compare them to the cell body. And then, another very important experiment was to demonstrate that those messenger RNAs that are, as we say, localized are actually made into protein. Because a persistent criticism was, "Ah, you can find mRNAs everywhere. Maybe they're just diffusing from the cell body and never made into protein." Another very important set of observations was thus using methods to show directly that those mRNAs are made into protein.

ZIERLER: For the last part of our talk, I'll ask a few retrospective questions, and then we'll end looking to the future. Just to reflect back on your time at Caltech, socially and scientifically, have you remained connected? Are you following what's going on at Caltech? Are there any collaborations you've had or you hope to rekindle?

SCHUMAN: I still am connected. I have dear friends and colleagues that are there, and I come back once a year or so. I don't know when my last paper with Dave was, but I think if we do anything new with the method, I will definitely talk to Dave. I still would list Dave as an active collaborator there. I have very fond feelings, and when I think about my colleagues there, they're a very important part of my life and my science. They're in my heart, for sure.

The Exhilaration of Bringing Chemistry to Life

ZIERLER: We can sort of decouple the terminology, what chemical biology is, where it originated. But just to use that broad concept, as you look back, where were you, your colleagues, Caltech really leading and defining the field in the way that Caltech does in so many research areas?

SCHUMAN: I would say that we were bringing the chemistry to life. The chemistry that Dave was working out, we were showing could be used to understand biological questions. Coming back to something I said earlier, we really showed the beauty of the method and applied it to a problem that was begging for this technology. I think you can say that about every aspect of the pipeline, the development, all the offshoots of what we call the NCAT technology. because it's really being used in a lot of different areas of biology to understand what's at the core of plasticity, be it normal plasticity or plasticity that happens during disease or malfunctioning states.

ZIERLER: Looking to the future, because your research is so fundamental, and because you're studying something so extraordinarily complex–it doesn't get more complex than the brain–what is the frontier for you? How do you visualize or conceptualize the big great unknowns in the field? And forever long you want to remain active, however you define your research agenda, 1 year, 5 years, 10 years, how do you want to make progress on redefining what that frontier is and what you can do in it?

SCHUMAN: I think the big enigma of all of this, for me, starting in learning memory was understanding that proteins lie in the heart of plasticity, and the plasticity that I'm interested in is learning and memory. And we know that human memories can last decades or a lifetime, but the substrates for those memories, the proteins, last days. How do you actually build a system that can keep information, can store information for decades when the building blocks last days? I view all the work that we've done up to this point as sort of essential for getting at that question. And now, I want to basically get back to it. I want to really try to understand how, knowing what we know about these unstable elements, the proteins and the mRNAs that fuel protein production, we can actually build memories at synapses from this information that we have.

ZIERLER: Just as an addendum to that question, how do you do that? Is it the drudgery of the lab work, and then you hit upon something amazing? Are there technological advances you're waiting for to actualize this? How do you actually get from here to there?

SCHUMAN: I think the technology is there. It's now up to us to design the key experiments that will shed light on this. That's what we're working on now. How can we take the methods that we've been working on and exploit them to visualize the full protein complement at a synapse and watch how it's maintained during memory? That's the goal.

ZIERLER: You're confident it's just a matter of getting in there and doing it.

SCHUMAN: I hope so. To be honest, along the way, we've learned so many things that I could just sit back and say, "Oh, that's fabulous." But I really do want to come full circle back to the question and mystery that got us here to begin with.

ZIERLER: This has been a wonderful conversation. You're most generous for spending your time with me. I want to thank you so much.

SCHUMAN: Thank you, David.

[END]