Chris Chang (BS '97), Bioinorganic Chemist, Sustainability Researcher, and Chemical Biologist

In explaining how the periodic table is the "North Star" of chemistry, it quickly becomes clear how Chris Chang has been able to pursue a fantastically wide-ranging research agenda over the past two decades. From bioinorganic chemistry to neuroscience, to energy sustainability and to proteomics, the Chang Lab has adopted an an approach that embraces commonalities in chemistry with the periodic table as a conceptual connecting point between seemingly disparate disciplines. And it all started with an eminent professor who gave him a chance.

After spending most of his childhood in Iowa, Chang moved with his family to California during high school, and a visit to Caltech as a prospective student sealed his decision to become a Techer. After focusing his interests on chemistry, Chang persisted in joining Harry Gray's lab, and for the rest of his undergraduate days, Chang was able to do real research in a tremendously productive research environment. After completing his PhD thesis at MIT, Chang stayed on to complete a postdoc with Steve Lippard, which served as a key entree to bioinorganic chemistry, and to his focus ever since in the broad study of the chemistry of life.

In his twenty years as a professor at UC Berkeley, Chang has kept front of mind the importance of creating opportunities for students and in conveying the excitement of discovery that is at the heart of all scientific research. Among his numerous and prestigious academic awards and honors, those most precious to Chang recognize his passion as an educator, which undoubtedly relates to his own experiences at Caltech.

The discussion below capture's Chang in a moment of career transition. In July 2024, Chang will become the Edward and Virginia Taylor Professor of Bioorganic Chemistry at Princeton University. Chang describes the opportunity in bittersweet terms; UC Berkeley has proved to be a terrific research environment, and he has loved his time there. But after twenty years, and in part, prompted by the dislocation we all felt during the pandemic, the time was right for a new venture and, undoubtedly, new research avenues to pursue. Whatever the future may hold, one thing is certain: Chang's love for the pursuit of knowledge will remain the North Star for his research.

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Thursday, February 29th, 2024. It is my great pleasure to be here with Professor Christopher J. Chang. Chris, it's wonderful to be with you. Thank you so much for joining me.

CHRISTOPHER J. CHANG: Oh, thanks. I really appreciate the time.

ZIERLER: Chris, to start, would you please tell me your current titles and institutional affiliations?

CHANG: I'm currently the Class of 1942 Professor at UC Berkeley in the Departments of Chemistry, Molecular and Cell Biology, and the Helen Wills Neuroscience Institute. I'm also a Faculty Scientist at the Lawrence Berkeley National Laboratory, as well as an Adjunct Professor at UC San Francisco in the Department of Pharmaceutical Chemistry.

ZIERLER: Lots to unpack there, because I know it's all substantive and indicative of all the research that you're involved in. Let's start first with the affiliations. Your professorship, is it one professorship that's split between the departments of chemistry, and molecular and cell biology? Is that how that works?

CHANG: Yes. My primary appointment is in the Department of Chemistry, with joint appointments in both molecular cell biology and neuroscience.

Studying the Chemistry of Life

ZIERLER: Is that to say that fundamentally you're a chemist who also does molecular and cell biology? Is that a good way to think about it?

CHANG: Exactly. What we do is, in a nutshell, is study the chemistry of life, and we want to understand life at the atomic and molecular level.

ZIERLER: Does that make you—I know there's a unique field called chemical biology, where it's chemists who can do interesting things with molecules that don't exist in nature to probe biological questions. Is that part of the story as well for you?

CHANG: Yes. We wear a lot of different hats. I would say that some people would classify a lot of the work we do in the lab as chemical biology. Other people would call us bioinorganic or bioorganic chemists in the more traditional sense. Then other parts of our research span into pure inorganic and materials chemistry as well.

ZIERLER: Tell me about the Helen Wills Neuroscience Institute. First, who is or was Helen Wills?

CHANG: Helen Wills was a major donor and alumni figure at UC Berkeley. I think that she was a big professional tennis player back in the day [laugh], but I'd have to go and look that up. But basically she always had an interest in neuroscience as well as education, teaching, and research at UC Berkeley. She endowed this institute, which has basically grown over the decades, to support neuroscience activities broadly on campus. One thing that's interesting about neurobiology and neuroscience at Berkeley is that we are just launching the first department of neuroscience this year. It's going to be under a larger umbrella, like the Beckman Institute, in how it interfaces with core departments of teaching across the campus.

ZIERLER: Now, that's interesting, Berkeley is such a path-breaker in so many ways. Is it somewhat late to the game in establishing a neuroscience department now?

CHANG: To be honest, yes, I would say that neurobiology has been a division within molecular and cell biology for 30 years. But as our understanding of the brain is really in its infancy, and with bringing together stakeholders across campus, especially chemistry, different types of engineering, as well as now data science, statistics, etc., and electrical engineering in particular, it's really a ripe time to form not only a department of neurobiology but a department of neuroscience. But it has been long time coming.

ZIERLER: As a member of the Neuroscience Institute, what is your interface with neuroscience generally?

CHANG: Basically, we are broadly interested in neurodegeneration, neurodegenerative diseases, and understanding the molecular basis of those processes, as well as new types of potential therapeutic and diagnostic applications from the chemistry side, so neurochemistry and chemical biology of the brain.

Interface with Biotech

ZIERLER: Thinking about human health and therapies, this might anticipate my next question. Your affiliation with UCSF, is that to further integrate you with the biotech and the translational world in the Bay Area?

CHANG: Exactly, and so because UC Berkeley doesn't have its own medical school, the initial idea was that UCSF was supposed to be a sister school and almost like a medical school for the Berkeley campus. But, of course, it's grown into its own super strong and independent biomedical research entity in and of itself. Having that cross-disciplinary appointment across the Bay really enables you to bring the basic research that we do on this campus at Berkeley, and to translate that to new diagnostics therapies.

ZIERLER: On a day-to-day basis, what does that mean, being at UCSF? Are you in the medical school? Are you talking with biotech start-ups?

CHANG: Yeah. We have a lot of different interactions across the Bay. From an academic perspective, that department, Pharmaceutical Chemistry, as well as Cellular and Molecular Pharmacology at UCSF, are the sister programs to the Department of Chemistry, and the Chemical Biology program we have at UC Berkeley. We share students. We collaborate. We have joint retreats. In fact, I did my first sabbatical, actually my first and only sabbatical, at UCSF, and so it has been great to integrating into that community. I would say that the biotech pretty much flows anywhere to any university in the Bay. But it's not, I guess, having joint appointments across different UC campuses has any sort of advantage or disadvantage per se in that way. But it does help you bump into more people who have MD degrees as opposed to our basic science campus.

ZIERLER: Chris, the one affiliation or the honor that you have that might be a little less substantive, the Class of 1942 chair, is there something special about the Class of 1942?

CHANG: Not necessarily, except that they were incredibly generous [laugh] to the campus. We have many sorts of class gifts that are given over the years. That class decided to support professors and their research and teaching missions. We're really grateful for the support from that class.

ZIERLER: All of your work within and beyond Berkeley in the Bay Area, I understand you've made a major life decision, and you'll be leaving this soon, and transferring.

CHANG: Yeah. It's bittersweet to talk about it, because we do love Berkeley, and we've been extremely happy and valued by the community here. But it's been 20 years since we started. I started here in 2004. Like any sort of scientist, you want to try new experiments, and look to the future, as opposed to what you're doing in the present. My wife, Michelle Chang, and I are both professors across different departments at UC Berkeley, and Princeton's made a really compelling and generous offer for us to move. We're going to take the leap, and move back East in the summer of 2024.

ZIERLER: Will you pursue a similar kind of dual affiliation that will satisfy your interests in both chemistry and biology?

CHANG: For sure! We're already in discussions with the allied departments in the Princeton Neuroscience Institute as well as the Department of Molecular Biology at Princeton. There's lots of great synergy between those two departments as well as chemistry. But it's also the proximity. New Jersey has a lot of contacts with the pharmaceutical industry, and so translating the basic research again to medicines. Princeton, like Berkeley, doesn't have a medical school, but there is proximity to both Columbia and all of the things that are going on in New York City as well as UPenn. It really provides, again, a brand new type of environment to explore. I think that what we're interested in is really pushing a lot of our work further into neuroscience as well as into translational applications of our basic science at this point in my career.

ZIERLER: It's a great opportunity for you to think about what's important to keep and to transfer over, and what are some new research avenues to pursue. On the former, first, the nuts and bolts of picking up a lab, are you taking your equipment? Are you going to get all new stuff? What is that going to look like?

CHANG: Actually, it's kind of like something borrowed, something new, so to speak.

ZIERLER: [laugh] Yeah.

CHANG: Basically the entire group is moving with us. They're ready to pack up and start a new adventure. We're actively recruiting new graduate students, undergraduate students, and postdocs at Princeton. But the current team is going to move almost in its entirety. There are a couple people that will stay behind, because of family considerations, but then after those obligations are done, they're going to move to Princeton as well. We are planning to take many pieces of the equipment. Some of the equipment has to be left behind because of my current affiliation as a faculty science with the Lawrence Berkeley National Laboratory. That is a Department of Energy lab. Therefore, that's US Government property [laugh], and so that will be obviously staying all at UC Berkeley and the Lawrence Berkeley National Lab.

ZIERLER: Now, of course, there's a National Lab at Princeton as well, the Plasma Physics Laboratory. Will you pursue an affiliation there, given your interest in energy concerns?

CHANG: I would say that, to be honest, we're going to be more freelancing the energy and sustainability research that we're doing. I would say that's exciting in its own way to do things from the bottom up as opposed to the top bottom, which is a lot of what happens in the Department of Energy and large government centers. Right now, we're most interested in using electricity to make compounds. Plasma research is not something that we've considered at this point. But, like all things, once you learn about something, you get interested in it, and so nothing's out of the realm of possibility.

New Directions at Princeton

ZIERLER: Chris, beyond just a new environment, and being open to what that's going to offer you, do you have well-developed ideas of the kinds of research that you want to move into, simply by virtue of being a professor at a different place?

CHANG: I would say that we want to delve more deeply into neuroscience, and probably move our studies into a broader range of biological models. We started with zebrafish, which are very simple transparent model organisms, one of the simplest ones that are so-called vertebrates (animals with a backbone). We've also done a lot of mouse work over the last five to seven years. I think that one opportunity is to really translate that, and move on to primate systems. Ultimately, we'd like to go into humans. But I think that there is a trajectory for us to be able to do so with the new move and a fresh new start.

ZIERLER: Chris, let's now delve a little deeper into some of the major research questions you've pursued in your career. One that's very obvious and interesting to me, your facility in both organic and inorganic chemistry, and the way that that allows you to ask fundamental questions about things like the brain to battery and energy storage. What does that tell us about chemistry that you can ask these questions about things that seemingly have no complementarity to them?

CHANG: I get asked that sort of question a lot. What we do is basically guided by the periodic table, and we really view that as the blueprint for the elements of life. A running theme in our laboratory is that we aren't wed to a particular part of the periodic table or a particular set of elements per se, because they're all important, and they all have roles to play, not only naturally within our bodies but also in the way that we interact with the world around us. I think that's one theme where you can imagine the biomedical research that we do, the chemical biology interface, as linked to the sustainability in our place on the planet. That's why we got interested in energy science as well. We've had these two parallel tracks, but they all come back to the periodic table. Whether it's inorganic chemistry, which has to do with non-carbon elements, particularly metals, or organic chemistry, where we're made of carbon, and so therefore that becomes front and center. We don't really have any biases, and so we're just so lucky to be able to recruit great students and postdocs from all over the world to really embrace this holistic approach to chemistry.

Origins of Life and the Periodic Table

ZIERLER: Chris, I wonder if you've ever thought about what—it's either called astrobiology or exobiology, on this specific basis of we need to keep a very open mind, not to be biased as to what life might look like elsewhere, and if your expertise in both organic and inorganic chemistry might be a very valuable perspective, for example, looking for biosignatures from telescopes, or samples from Mars, whenever they get back home, I wonder if you could reflect on that.

CHANG: That's a great question. I would say that, obviously, origins of life is a huge burgeoning field of chemistry. There's really no answer, because it becomes a bit of chemistry to philosophy of what is life, and what is an organism going to look like, and what is the minimum set of elements that one needs? What I would say is that it all comes down to energy. It's the sustainability of life, basically. You need energy to self-propagate. We think about that in terms of carbon. Of course, in energy science we think about that too in terms of greenhouse gases, with too much CO2 in the atmosphere. But even that question on a terrestrial scale is an imbalance of elements. Too much carbon in the atmosphere in the form of CO2 is reciprocated by too much nitrogen from nitrates and nitrites and other nitrogen oxides that pollute the soil and water from over-farming. To get back to the astrobiology question, what you can think about is this question: is there this mosaic set of other types of elements out there that will cause things to go out of equilibrium? Then if they're out of equilibrium, then obviously that propagate certain types of signatures. For example, Frances Arnold's group has been working on a lot of silicon-based chemistry these days, and it's just one element down in the same family of the periodic table. In certain instances, it wouldn't be surprising that elements like silicon would be incorporated more broadly in other types of life forms in terms of pure speculation, in terms of the basic chemistry.

ZIERLER: I wonder if you think about origins of life, from a chemistry and biology question, the way that cosmologists might think of the Big Bang and time equals zero; that there's an inherent unknowability about the very beginning, and if that bothers you?

CHANG: No, actually, it doesn't. That's because again we go back to this North Star of the periodic table. Humans, we create new elements. We can mix and match them. The periodic table is always expanding. Even with a relatively limited number of elements, there are only a little over 100 elements. But everything around us is made up of those elements in different combinations. Really, chemistry is something where you can see the unseen. Everything that we're doing, this computer screen that we're talking through, the water that I'm drinking over here, the food that we eat, the air that we breathe, they're all elements in different combinations, different ratios, different amounts.

ZIERLER: An overall question about your research motivations, and if there's a narrative over the course of your career. Of course, it all starts with basic science, with curiosity-driven research, but both in your interest in translational biology and sustainability, broadly conceived, if sustainability is the translational science of chemistry, to some degree?

CHANG: I actually agree with that. I think the thing is we've been interested in understanding how life works at the fundamental level. That new knowledge, I think, it is gee-whiz science, and it has value for understanding our place as a society on this planet. But of course you want to improve upon the existence of everybody for the benefit of society. I think that's one of the areas that students especially are really keen on studying, which is our own sustainability. I would say that a lot of times when people talk about translational chemistry, they think about medicines as the most common example, like the first antibiotic or the first precision cancer drugs. Now of course neurodegeneration and aging is a huge topic. But translational chemistry can be more broad than that. I think that the energy question and sustainability in the environment is definitely translational chemistry in and of its own right.

ZIERLER: Now, for you, are these kinds of questions, where the starting point might be societal benefit, is this a post-tenure pursuit, or are these things you've explored from the beginning of your faculty career?

CHANG: I would say it's been at the very beginning. I think the thing is in order to do things that are applied, you have to start with basic. It's like the opposite of the alphabet. You have to actually do B before A. [laugh]

ZIERLER: [laugh]

CHANG: I think it's something that we've had a long-term vision, in which we do want our research and knowledge gained to be of benefit to society. The most important thing of course though is the students that you teach and then the researchers that you train in the laboratory. In the end, a professor is a teacher that has different hats to wear. But I think that we can teach our students, we can teach ourselves, and then hopefully we can teach society and our community the value of this type of scientific exploration.

ZIERLER: Chris, I wonder if you are not only a user of cutting edge technology but you're also a builder, if the kinds of things that you pursue require instrumentation that simply can't be purchased off the shelf?

CHANG: I would say that we do things on the atomic and molecular scale. In some ways, you can think of chemists as atomic and molecular engineers. We really build things not necessarily in the way that you would build an instrument, but we're actually building things atom by atom, molecule by molecule. That's the way we view science. Even from the perspective of, say, you use a microscope that's commercially available, but the sort of probes that we develop basically enable you to create new types of experiments that couldn't be done if you were limited by what's commercially available. The hardware, per se, for us is the chemistry, the molecules and the materials that we put together in the laboratory that create the experiments.

ZIERLER: How important is simulation in your research, and does that get you closer into AI and machine learning?

CHANG: That's a great question. What we're getting into is trying to use limited data sets in order to extrapolate different types of trends. We have this project where we're looking at the effects of single atom marks on our proteome. If you think about a genetic code, genetic code is DNA. Then there's an epigenetic code that's not inherited, but that is environmentally controlled on that DNA or RNA. That leads to making all of the proteins in your body, as you go from DNA to RNA to protein, as the central dogma of biology. What we've been interested in is that are there additional marks on all of the proteins, your proteome, within the body? We've been interested in single oxygen marks. The idea is that then we would like to be able to interface that with more deep learning to understand what the code for writing is and erasing those types of marks on our proteome.

ZIERLER: When you look at translational biology and therapies and drug discovery, coming from the periodic table perspective, as you've explained to me, are there deeper questions that combine cancer and neurodegeneration and metabolic disorders where you're taking a more holistic approach than a clinician specialist might?

CHANG: Yeah, exactly. Essentially, it's a Goldilocks principle. Some elements, you need the right amount. Too little is bad for you. Too much is bad for you. That's why we want to study things, as I said, not at just a molecular level but to actually understand them at the atomic level. We want to study individual atoms and where they're attached to in the proteome, and does that give rise to larger-scale behavior at a solid level, at a tissue level, and then moving on to the whole living being? I think taking that approach as opposed to picking a disease is what makes what we do different, because the disease vulnerabilities, the druggable hotspots, or the new types of diagnostics or therapeutics that will go towards that, like a precision medicine, are going to be based on our elemental patterns. Can we see this mosaic pattern of life, and then pick out, like a needle in a haystack, the vulnerabilities? Sort of like pulling a thread on a sweater, and watching it totally unravel; although I guess that sounds like one of these 1990s Weezer songs—

ZIERLER: [laugh]

CHANG: —when I was a Caltech undergraduate. [laugh]

ZIERLER: Chris, I wonder if you could explain what metal signaling is, and what you're able to do with this technique?

CHANG: Basically, metals are nutrients. They're more commonly known as minerals, if you talk to the lay person. If you take a Flintstones Vitamin, you see that there's iron, there's copper, there's zinc, there's magnesium. To the lay person, those are called minerals. But to chemists, those are metals. We think about metals in a large scale, like forging cars and buildings and airplanes. But in every single one of the cells in our body, and in every living organism across all kingdoms of life, we require a quota, a cocktail of these different types of metal elements. Now, typically the field thinks about these as interacting with either your DNA or RNA to stabilize the three-dimensional structure, or proteins where a metal will bind to protein, and catalyze reactions mediated by that protein. It's a gain of function. Our work has really broken that narrow paradigm because, if you think about it again from first principles, you bring elements together in a certain ratio, you can either increase or decrease function. You can increase or decrease fitness, if you think about it from a cellular perspective.

The element can bind anywhere along the linear or three-dimensional sequence, and so the concept that we've come up with is metalloallostery. Allostery is a common biochemical term, where you have something bind to a protein that's not at its active site. It's called an allosteric site because it's outside the active site. But something all the way out here can affect the active site, and turn on or turn off its reactivity, just like a thermostat or a light switch that's not binary but a light switch that's like a dimmer switch, so you have full control. We found that metals can do that. Metals can bind, and either turn on or turn off the activity of a protein. It can make it stronger or weaker in terms of the phenotype that it can elicit in a cell. Then that has broader applications and implications for behavior. For example, we've studied roles of copper as a signaling cofactor. That's an allosteric regulator. We found it controls everything from sleep, cycles of sleep, quality of sleep, to your ability to process food, and gain weight, and burn fat, to cancers, the switch between whether a cancer would be a local cancer, a primary tumor, to one that metastasizes. When it metastasizes, obviously that's where it really is bad for you, and that's the outcome. These single atoms of nutrients that you would get out of a Flintstones Vitamin bottle, put in the right place or put in the wrong place on the right protein or the wrong protein, or too much on this protein A but not enough on protein B, is the code that we want to break and decipher, like a Rosetta Stone.

Molecules and Handshakes

ZIERLER: If you can help untangle your work in activity-based sensing, what is the activity, and what are you sensing?

CHANG: This was another concept that was actually the first project that we launched in the laboratory. As I said, this long-standing interest in studying atoms and really small molecules, one of the challenges that we came up with at the very beginning is we wanted to study extremely transient molecules that were at very low concentrations. These are called reactive oxygen species. Each time you take a breath of air into your lungs, it gets distributed throughout your body. Your heart, arteries, and veins pump the blood in and out throughout your entire circulatory system, and it carries oxygen. Oxygen gives you energy to power the mitochondria in your body.

The way it typically works is your body is a perfect fuel cell. You breathe in oxygen, and you burn that oxygen in your body, and water is the only byproduct, which is a pretty good one if you're a living human being. But what happens sometimes is that your body is not perfect, and you generate what are called reactive oxygen species, where the oxygen gas isn't completely reduced to water, and you release tiny amounts of these reactive oxygen species. That's what we wanted to detect, because that's a source of what is called oxidative stress, which can cause free radical damage. But, at the same time, when we started our laboratory in 2004, there was a growing appreciation that this wasn't just a byproduct of evolution, but it was something that actually could be used by the body in beneficial ways, kind of like fire. Uncontrolled fire is terrible. But fire that's well controlled can be used for cooking and heating. We wanted to detect these reactive oxygen species, but they're very, very transient. Long story short is that these molecules are really small, and if we wanted to make a lock and key, like a handshake, it's very difficult. You want to have the right size, the right shape. What we needed was a way to capture these molecules. We decided to use catalysis to do so. That's the activity that we're sensing. The molecule is sensed by its own catalytic activity.

ZIERLER: Chris, you mentioned proteomics. Of course, this is a well-developed field. It's an enormous field. What is the state of the art in early 2024? What are the big questions? How are you pursuing those questions?

CHANG: I would say that there's two things. Detection in terms of proteomics, the instrumentation and the techniques are getting better and better for taking smaller and smaller amounts of sample in order to detect protein. One big challenge, and I think it's akin to the Human Genome Project, is actually to do single-molecule protein sequencing. I think that's something that we and others in the field are really interested in pursuing. That will give rise to a proteome code, just like you would have a genetic code. I think that's one of the biggest outstanding questions. Now, beyond that, the interesting thing about proteins is that we only have 20,000 genes in the human body or so that would give rise, say, to about 20,000 proteins. But it turns out that there are modifications on those proteins, kind of like what I talk about, the single-atom modifications. But you have phosphorylation, putting phosphate groups on, or glycosylation, putting sugars on. You have lipidation. You have methylation. All of these modifications actually turn 20,000 proteins into millions of what are called proteoforms inside each and every one of our cells. Now you understand that it's a human genome project, but then it's grown exponentially in scale. When you go from four nucleic acid bases to twenty amino acids, and then each one of those amino acids can be modified in many, many ways, then it multiplies the problem to a huge scope, where the complexity is fascinating. I think it is fascinating. I would say the proteome code and going beyond the proteome code is one of the biggest challenges in this area today.

ZIERLER: That anticipated my question. Of course, the Human Genome Project got started just at the point when biology started to become really computational, and there were computers powerful enough to deal with that amount of data. Here we are 25 years later. Is the computational power there to make a proteomic human project?

CHANG: To be honest, I hesitate to say we have the computational power yet. I think what we do need is we do need deep learning, because the amount of data that we have is relatively so small. I think we're going to have to start with simple model organisms with fewer modifications and a smaller genome, to begin with. Just the way that you can do genomics on bacterial systems in parallel, hundreds of organisms at a time, I think for true proteome code, I think we're going to have to start at that before moving on to, I would say, a human proteome project, which I think should be something that should be accelerated in the coming years.

ZIERLER: That's sobering. You're at Berkeley Lab. You see the very best of what the US Government can throw at a problem in terms of computational power. I'm sure this is far afield from your own research, but I'm always interested at Caltech inquantum information and quantum computers. There are these foundational questions about what a quantum computer will be good for. When that comes to pass, is this the kind of challenge in biology for which a quantum computational approach might be relevant?

CHANG: I think that it's got to be all hands on deck, because the information, the amount of data is so huge. Being able to essentially miniaturize and multiplex is going to be important. That's why I feel as if the AI and machine learning will probably be a little bit ahead, because you can extrapolate on limited data. I think that this is basically where we are right now. We're just at the beginning of this frontier of a true proteome code. I think that the next step for us is to see if we can extrapolate what little data we have to make those leaps and bounds.

ZIERLER: I don't want to make it, you know, you said it almost as a throwaway, proteomic code and beyond. What is the beyond? What does that look like?

CHANG: I think the thing is when you think about a genetic code, you don't think about it just as like your genetics, which lead to inherited traits. But the proteome code and genetic code, getting down to single cell level, is another direction for the field, because as we evolve to more and more complex organisms, each cell is specialized. Each cell then has its own fitness tested all the time. Even from the genetic code, it's not so simple. You do have to end up going from the genetic code to the single cell genetic code. [laugh] That's another huge direction on another axis. If you think about the proteome code which, I just told you, is going to be much larger, then that one also has to be brought at some point down to the single cell level.

ZIERLER: Is this to say, you know, not to get way too far ahead of ourselves, but where there's a certain level of frustration in how much there is to do in understanding Alzheimer's, in cancer therapies, is the proteomic code, is the idea that this really is going to unlock answers that are certainly not available to us now?

CHANG: Yeah, but I actually view it more in an optimistic way. I think that's what makes science so exciting is that you do want to do something that no one has done before, or observe something that no one has observed before. Since technology is always moving forward at such a rapid pace, I think that there are huge opportunities for our generation and the next generation to get involved. The great part about science and at least for academics that do open publishing, you can read about what's going on anywhere across the world at any time, from your desktop. Whereas before the digital age, it really was very slow for information to get disseminated.

ZIERLER: Chris, your work on artificial photosynthesis, of course, one of the key problems there is scaling. Where for you is it an interesting laboratory question, and where do we make this so that's a technology that really helps on a global scale?

CHANG: My philosophy on it is distribution. I think we want to think about it not in the way that the industrialized world thinks about it but a distributed energy, because there are many parts of the world that don't have the same infrastructure. Can you run small household appliances? Can you run things like getting enough clean water to wash your clothes or cook your food? Can you heat your home? I think that those are the sorts of scales. It's about distribution, not necessarily scale, in terms of something very large for these types of devices now and in the future.

Midwest Roots

ZIERLER: Chris, let's go back. Let's establish some personal history. How did you hear about Caltech? Why did you choose Caltech?

CHANG: [laugh] That's a great question. I grew up—I was born and raised in the Midwest. I was born in Iowa. We moved to Indiana when I was 2. Basically I grew up in a cornfield [laugh] or right behind a cornfield. I would say a place like Caltech was really, really far away.

ZIERLER: How did your family get to the Midwest?

CHANG: My parents immigrated from Hong Kong via China, and this was like the late '60s. They settled in Wisconsin. My parents met in La Crosse, Wisconsin, and got married. My dad was a student at Iowa State. I was born in Ames. Then family got jobs. We moved to Indiana. Basically grew up in a really, really small town. The joke was that we didn't have a street address for the first 10–12 years of my life. It just said, "Chang Family Rural Route 6," and it got to us, the mail [laugh], sort of like a pony express.

ZIERLER: [laugh]

CHANG: We moved to California. Actually, my dad passed away when I was in high school, so we moved to be closer to family in California, to the Bay Area. I tagged along with a friend that was going on college visits. His dad was a legacy at MIT, and so he wanted to visit MIT and Caltech. We took a road trip down to Southern California. I would say the first time I saw this place, I was like, "This is really amazing." [laugh]

ZIERLER: [laugh]

CHANG: It was really idyllic, and people were happy and just doing all sorts of interesting things. I ended up applying. It came down to a choice between coming to Berkeley as an undergraduate or going to Caltech. I have to be honest, it was the financial aid. I got enough financial aid at Caltech that it was actually cheaper with the work study, and I was able to go. It was a coin flip, because even though I'm a professor at Berkeley, I could have actually been a Berkeley undergraduate, and it was just fate. Two totally different types of places. But I would say once I first stepped on campus, it was definitely the place to be for me.

ZIERLER: You arrived in—was it '93?

CHANG: Yep, the fall of '93.

ZIERLER: What were your interests at that point? What did you want to pursue?

CHANG: That's why it's the third time's a charm. I was not a chemistry major. [laugh] I actually came, like most Caltech undergrads, to do engineering. I went through a couple of engineering majors that didn't quite stick until getting into chemistry. It was actually two things. The first thing was the old, at that time, the old Mead labs, the undergraduate teaching labs. One of the laboratories was to make the original inorganic coordination compounds, or they're called Werner compounds. You get these beautiful purple and yellow and orange solids. You're cooking them, and then you see these totally different colors. It's just a question of rearranging the same atoms, and how they're bound to the metal. I was like, wow, that's really neat that I can see it with my eye but know the invisible sort of code for why it makes the color that it makes. Then I took a class by John Bercaw. I think Bercaw has recently retired.

ZIERLER: Yeah.

Caltech and Learning from Harry Gray

CHANG: There's this famous Chem 112 class. He was a fantastic teacher, and really just explained why we were seeing what we were seeing in the real world. I really got hooked on chemistry. It's seeing the invisible, so to speak. Then I basically asked everybody in the department for a research position, and got rejected from everybody [laugh], except for Harry Gray. [laugh] Of course, it's like you're this kid. You're knocking on professors' doors at the time like, "Oh, do you have room for an undergraduate?" I had the Chicago Cubs hat on.

ZIERLER: Aha.

CHANG: Growing up in the Midwest that was a team I had followed. And it turns out Harry is a Cubs fan. Harry told me to come back the next day. But each day, he told me to come back five minutes earlier. [laugh] I think that he maybe was trying to get rid of me at the time, but I just kept coming back. Then finally, I think it was like the third time, he says, "Oh yeah, you're in. Go and"—you know Harry. He's just incredible.

ZIERLER: Yeah.

CHANG: Then I started research with Harry, and worked with his lab the rest of my undergraduate days there.

ZIERLER: What was the Gray lab doing at that point?

CHANG: The Gray lab was very much full force into energy science, and looking at how electrons, electricity moves in proteins. At the time, one of the big projects was how that influences how a protein folds. There's energy conversion, and then how that energy is manifested into this three-dimensional structure of proteins. But it turns out that I actually had a very retro project. I worked personally with Harry on a project, which was essentially his first project as a postdoc back when he was in Copenhagen back in the early '60s. Because I liked colors, we worked on these beautiful green-colored emerald compounds that had multiple bonds between them. Harry, in one of his first famous papers in the first issue of Inorganic Chemistry back in 1962, was the electronic structure of vanadium attached to oxygen, a vanadyl species, and the bonding behind that. That basically was the launch of what is now called ligand field theory, a type of molecular orbital theory that has to do with metals, and how they bind to other atoms and elements. We worked on a manganese nitride or manganese nitrogen-bonded analog, and published some papers. I really learned chemistry from the best, going all the way back to his work in the early '60s.

ZIERLER: This is a Caltech undergraduate doing real research in a real lab?

CHANG: Exactly. With the class being so small, we only had I think 10 undergraduate majors in my year, so the Chem Club was much smaller [laugh] back then, I would say, and so that was really formative. At Caltech, there are lots of classes. People have to take so many classes, and the homework sets are long, the infinite time for exams. [laugh] Basically professors are like, "Go ahead. [laugh] Try to answer these questions." I think it really promoted the ability to think outside the box, and research really resonated with me, much more than the problem sets did.

ZIERLER: Chris, on the social side, what house did you live in, and what kinds of activities were you involved in?

CHANG: I was at Page House as an undergraduate. To be honest, it was at the time known for a lot of drinking. [laugh]

ZIERLER: The party house?

CHANG: It was a party house at the time. But I think people still did their homework and worked pretty hard but had a great time. I played on the Caltech basketball team. I did some work in library, the Millikan Library. I guess that's going to be renamed at some point.

ZIERLER: It already is Caltech Hall.

CHANG: It was a great group of people. The house system I think is unique to Caltech, and it really builds bonds. This sort of almost like a Harry Potter sorting hat type of week that occurs was really great. I felt like I found the right home or house for me, and really enjoyed my time, and made a lot of friends. One of the last times I went to Caltech was a long time ago, but it was for a wedding at the Ath for a classmate.

ZIERLER: One of the best places to get married! [laugh]

CHANG: For sure.

ZIERLER: Chris, a more personal question. Growing up in the Midwest, you have a flat American accent. Coming to California, did that reconnect you with your Asian background at all? Did you think about those things?

CHANG: Yeah, actually I did. It was interesting, and I even wrote it in my college essay at the time, because now we come full circle of the way the world is right now, and we like to think that people aren't othered, but they still are.

ZIERLER: Sure.

CHANG: My family grew up in a place where I found out early on that there's no such thing as racism with a singularity. Racism really only occurs with a minority, because the singularity is not threatening enough to upend or change the order of things. We grew up as the only Asian family anywhere around at all, and it was a very homogeneous population. But I actually faced relatively little racism as a kid, unless we were traveling with the baseball team to other towns. That was worse then. But everybody, in such a small town, everybody knows each other so they can actually see each other as people. Obviously, as I said, being a singularity, that's non-threatening. Moving to California was really interesting because on the outside, I look like a lot of people in California. In fact, my accent has grown to be more Californian over the years. I used to have a pretty strong twang, growing up in the Midwest. You look like everybody but, at the same time, you're a totally Midwestern type of upbringing, which is very, very different than California. That was an interesting experience, being at a place like Caltech because now you go to college, and people are coming from all over the world. Even though it was a small place, I think it was the right fit. If I had gone to a place like Berkeley, it almost would've been like a sensory overload [laugh], I would say, for myself, my own personal growth over time. But it is interesting that it was something that I realized pretty early on.

Formidable French Interlude

ZIERLER: As you were nearing graduation, recognizing the value of chemistry in industry, for example, did you ever think about going for a job? Were you always on the academic graduate school path?

CHANG: I did want to go to graduate school, but I didn't know what I wanted to do after that. Like a lot of Caltech undergrads, I had a little burnout. We had to work really, really hard, and so I was ready for a break. I took a gap year before starting graduate school. I applied and was accepted. I got to do a Fulbright scholarship in France, in Strasbourg, France, for a year. I had never been to Europe before, and so it was just a big leap. I guess, in the end, like a lot of things, there's not a great reason. It was just a feeling of wanting to see beyond where I was at the time. I'd moved from the Midwest to California, so I figured I might as well see a different part of the world. Then it turned out that, I guess, what was it, maybe 15 years later, the mentor, the professor that I had won a Nobel Prize. [laugh]

ZIERLER: Oh wow. [laugh]

CHANG: It was Jean-Pierre Sauvage, and he was just the nicest guy. This is like the World Cup year 1998. He picks me up from the airport with his wife. Drives me home. The laboratory had already rented me this flat overlooking the cathedral. I just lived there, did some chemistry, traveled Europe during the weekends, watched some of the France matches in the early stages in the World Cup at the beginning of summer, and then started graduate school. That's part of the reason why I wanted to try a different part of the country. I chose MIT, so went to Boston [laugh], and was there for graduate studies.

ZIERLER: Now, did you defer admission, or you applied to grad school while you were in France?

CHANG: No. I deferred admission, because I didn't know whether I was going to get the study abroad program. I applied to both at the same time, and deferred admission.

ZIERLER: Were you already thinking about the interface of chemistry and biology? Was that a starting point for you at MIT?

CHANG: Yeah. I would say that it started in Harry's group at Caltech. I think that Harry is so steeped in the fundamentals of chemistry, and was really such a wonderful teacher that I felt that chemistry doesn't have to be put in a very narrow box. At Caltech, you have a lot of people that are polymaths. They're really good at a lot of different things. Then there are other people that are extremely good [laugh] at one thing, especially the people who do math. [laugh] It was just something that I was interested in. Just going to France, I already had basically two different types of research experiences before showing up to graduate school. In graduate school, I was very interested in energy science, way before it became popular. I think in the late '90s, gas was still probably like 64 cents a gallon. But I thought at that time, it was just really interesting to think about sustainability. That's why I chose the PhD advisor that I had at MIT, who has Caltech ties. It was Dan Nocera—

ZIERLER: Oh yes.

CHANG: —who was one of Harry's graduate students in the early '80s, and so it was full circle with that. I saw Dan give a talk, and was just blown away, and was like, oh, I want to work on energy science for my PhD. That's what we ended up doing. We did fuel cell research, and then bio-inspired type of catalysts mimicking enzyme active sites for looking at oxygen consumption. For me, it was a great experience. Boston obviously is a wonderful place for students. There's just so much young people energy in the town.

ZIERLER: Tell me about Dan's style as a mentor. How was he in guiding your dissertation?

CHANG: Dan is pretty hands-off. He lets people run with their own ideas and passions. But he is extremely supportive. I think that he was always there to help discuss big-picture ideas, and resources were never a question. Therefore anything that you needed, he would try to provide for the crazy ideas that we were trying.

ZIERLER: Now, it's a different stage in your life. You're a graduate student; not an undergraduate. How would you compare though the research culture at MIT, based on what you saw at Caltech?

CHANG: Research cultures change over the years. I would say the Caltech culture was much more collaborative than the MIT culture, at least at the time. I don't want to make it sound negative—

ZIERLER: Of course.

CHANG: —on my alma mater. But I think at Caltech, I went from a place where everybody knew each other and everybody by sight. Whereas MIT is a bigger place in a bigger town. I think it was much more engineering dominated. Whereas Caltech, I think, has much more of a balance between science and engineering. It was a different experience, but still it was an awesome place to do research.

ZIERLER: Now, you emphasized your interest in sustainability and energy issues. Did you also keep up on the biology side of things in graduate school?

CHANG: Yeah, so basically just by the literature and the seminars. I didn't do anything that was biological in my PhD. I really did pretty hard-core chemistry, sustainable catalysis. I met my wife Michelle at MIT. We were grad students together. Then when it came time to think about a next step, I was thinking about a postdoc [laugh]. Because we were getting married, we wanted to obviously stay in the same place. I applied to Steve Lippard's lab at MIT for a postdoc. At that time, we're doing all the wrong things for a two body career.

ZIERLER: [laugh]

Early Days of Biotech in Cambridge

CHANG: You're not supposed to get training grad school postdoc at the same institution in the same department. You're not supposed to take those considerations, husband and wife living in the same place. You're supposed to get your records and résumés to a certain stage, and then go on the open market. But I think that for us, we chose life first, and science gives you opportunities. That's when I really went back, I would say, into Steve Lippard's lab and studied bioinorganic chemistry. They're synonymous. He's most famous for the anti-cancer drugs that are based on platinum that are like testicular, ovarian cancer. He identified and elucidated all the mechanisms of action, and how they serve as DNA-damaging agents. That's the way that they work. Like 95% of all testicular cancers are now cured, and they're all platinum drugs.

ZIERLER: Wow.

CHANG: It's a huge success. If other cancers could be like that, in terms of that efficacy of treatment, it would be great. But Steve was interested in chemistry in the brain as well. I got a taste of it in my short time in his laboratory, because he was studying a zinc as a calcium surrogate. Calcium signaling is very abundant in cells in the brain as well as in your heart for transmitting information. But certain cell types in the brain had a lot of zinc in them. We studied some of those processes.

ZIERLER: All of the great hospitals in Boston, was that an asset for you as a postdoc?

CHANG: I didn't spend enough time as a postdoc in order to really interface with a lot of hospital researchers, because the imaging that we were doing was more cell-based imaging. Then I think future people in the laboratory went more towards the translational imaging, like MRI or PET. We've been able to do that in my own independent faculty career. But as a postdoc, it was just too short of time to take advantage of those opportunities.

ZIERLER: What about biotech? Was Cambridge already becoming a hub at that point?

CHANG: It was very, very, very early days. If you go back to Third Street and Binney, there was almost nothing except for the Marriott Hotel at the time.

ZIERLER: [laugh]

CHANG: Biogen was just getting up and going, but there was almost nothing else at that time. Now it's amazing to have watched it grow. Novartis was still the NECCO Factory at the time—

ZIERLER: Oh my goodness.

CHANG: —like the NECCO wafers.

ZIERLER: This is only like 20-some years ago. It's amazing.

CHANG: Exactly.

ZIERLER: Chris, the duality of your time at MIT, having both the energy and now thinking more about biology and translation, when it came time to go on the job market, what positions did you think about applying for? What was most exciting to you, and how would you market yourself?

CHANG: It was something where I wanted to do something of both, and I thought that, technically, the closest thing that I could be hired as would be as an inorganic chemist, and so I self-identified as inorganic chemistry. But then the proposals were definitely something that was a bit out of the box at that time. We had proposals in both areas; really wanting to understand metals in biological systems as well as using elements for sustainability, and catalyzing artificial photosynthesis.

ZIERLER: Where would you apply? What was compelling to you?

CHANG: Where? [laugh] I'm not sure if this should go on a transcript. But I was asked to apply to two places: Caltech and Berkeley. When professors from both institutions came to give seminars when I was still a graduate student, they asked me to send in an application, so I only applied to two schools. Then I flew back here to do two interviews. I did not get the Caltech offer, and I got the Berkeley offer, so it was like the opposite. Then I took the offer—

ZIERLER: An easy decision for you?

CHANG: Easy decision; I took the one offer that I got. To be honest, probably if I had gotten the Caltech offer, I would have definitely gone to Caltech.

ZIERLER: It completed the circle from the choice that you faced as an undergraduate?

CHANG: Yeah. It worked out really well. Obviously, when you hire people, it's the right fit for the department at the time. But I got really lucky. I think it's really stressful to apply for a job, and I didn't have to [laugh] do a full search.

ZIERLER: Nowadays, the buzzword is "interdisciplinarity."

CHANG: Right.

ZIERLER: As a junior faculty member at Berkeley, if not the name, was that sentiment already well established?

CHANG: Yes.

ZIERLER: Were you in good shape in terms of what you wanted to pursue?

CHANG: Yeah. It turned out to be the perfect fit. The great thing about Berkeley is that it is a big, big school. What it means is that, especially if you're doing interdisciplinary science, I had so much support. I still have support. But early on, it was really important to talk to collaborators in neurobiology, collaborators in materials science up at LBNL, and then just the breadth of the department, the people at the time. When I was hired, it was this huge, huge hiring spree by Berkeley in the early to mid-2000s, because it's kind of like children of the Baby Boomer age. At that time, I think we had 10 or 11 assistant professors. It's a big department, but we had turned over the faculty by almost 25% in my pre-tenure days. I think that sort of energy and excitement, everybody coming in with new ideas and new directions, but everybody being really complementary in terms of the areas of expertise was really exciting. I would say it was a golden era for the department at that time. Budget-wise now you can't hire that many people.

ZIERLER: Chris, tell me about setting up your lab. Let's start with the instrumentation. What was most important for you?

CHANG: [laugh] The most important thing was space. We only had about 800 square feet of space. We had to fit glove boxes, fluorescence instruments. We didn't have room for the microscopes that we needed at the time, so we had to use campus facilities. It was just about packing in the people. [laugh] The main thing about setting up the lab is it's not the equipment; it's the people. For me, that was the key. We outgrew our lab quite quickly, because of the great people we were able to recruit. One of my first grad students who joined the lab in the first year is now my current colleague Evan Miller in our department. If you're getting Berkeley quality faculty [laugh] in your first class of students, then I think that makes your job a lot easier. In the first four years, I think, I want to say something like eight or nine of those students are now running their own laboratories. It was something like 80% of the students went on to become professors from that initial time, because they were just interested in science, and then they saw how exciting it could be, and they wanted to lead their own teams.

ZIERLER: To go back to the translational societal impact, the early 2000s, now climate change is becoming a significant concern, the Bay Area is becoming a biotech hub. You mentioned this is right at the beginning of your faculty career. How did you balance those dual interests in basic science and translational research?

CHANG: That's a great question. I would say that, I'll be honest, it may or may not have been the right thing to do, but I siloed them. For the energy science, we really leveraged our Lawrence Berkeley National Lab appointment. I think that we really wanted to focus on basic science, because that was funded by the US Government. For the past two decades, I think we've really focused on fundamental questions without thinking about the device that one would put it in. I think that's borne fruit; large-scale programs have been launched at LBNL. One of the joint ones was the JCAP, LiSA types of programs. But there were ongoing programs at Berkeley the entire time, so you didn't necessarily need to be part of a hub in order to access that environment.

Then in terms of the chemical biology research, we've always been supported both by the Federal Government, NIH, and then that was supplemented with other support from Howard Hughes Medical Institute over the years, but lots of local industry and biotech. Everywhere from Agilent to Merck to Genentech have all provided support over the years in that type of ecosystem. We're in two different worlds, so to speak, that didn't match, per se. But it all still worked, because the students in the laboratory choose your own adventure. Which direction do you want to go into?

ZIERLER: Would students come to work with you, thinking that they could go between the two, even if you had them siloed? It's still one professor. It's still one lab.

CHANG: What I mean by "siloed," it was really more, I would say, the people that I interacted with. Like, people from Novartis or Genentech would never come up to Lawrence Berkeley National Lab, and give a seminar, for example. But the students actually all worked together. There were several students that went back and forth, that switched, depending on their project interest and what they wanted to do afterwards.

Foxes and Hedgehogs in Research

ZIERLER: You talked about, at Caltech, there's polymaths, and there's people who are really good at hyper-specializing. I'm always interested in the politics, the culture of tenure, and what to emphasize, and when it's about breadth, and what it's about depth. How did you manage all of those things when your time came up?

CHANG: That's a good question. I would say that you shouldn't have a strategy for that. You should be the best version of yourself. That's always the advice that I give. They call it being a fox versus a hedgehog. Foxes can do a lot of things quickly. A hedgehog kind of digs in. Both are valuable in science, and one is not more important than the other in terms of pushing the entire field or fields forward. For tenure, I think my experiences for my own self is that I was always encouraged just to do what I thought was the most interesting. As we moved forward at Berkeley, I've seen successful tenure cases be either a polymath or someone who sticks with one topic.

ZIERLER: How does this affect the chronology, the various appointments that you have? I meant to ask at the beginning, did your professorship in molecular and cell biology, was that from the beginning or that came later on?

CHANG: That came later on. At the very beginning, I was a chemistry professor as well as a faculty scientist at Lawrence Berkeley National Lab. Then I got the neuroscience appointment after that. Then after that was UCSF, and then after that was molecular and cell biology.

Imaging and Neuroscience Focus

ZIERLER: What was the carryover research from MIT that got you into neuroscience at Berkeley?

CHANG: As I said, I think really looking at zinc as a calcium surrogate was an interesting question. It did teach me how to do cell culture and microscopy, and so those were technical skills that I was able to bring to the lab as an assistant professor. But really then it led me to more reading. One of the original proposals of the laboratory, which is basically what we're still working on, is this question of the elements of life. It turns out that the human brain has more elements at higher concentration than any other part of your body. It's just a very simple fact. The question is, why and how does that work?

ZIERLER: The emphasis on metals in thinking about neurodegenerative diseases, so it's very fascinating because, as we're told repeatedly, Alzheimer's and Parkinson's are not inevitable results of aging, and yet they're concentrated in the elderly. How do you unravel that, from your perspective?

CHANG: What I would say is that aging is a risk factor for disease, and it has to do with cell viability and cell fitness. The way that we view things these days is—and that's why I said we're pretty disease agnostic in the way that we approach problems, because in neurodegeneration, you want to keep the cells alive and growing. In cancer, you want the opposite. [laugh] You don't want those cells to grow and divide. Finding out what causes something to live and die at that level, and how it interfaces with its neighboring cells, is the first stage to understanding atomic molecular basis of disease. The great thing about metals is that, although the actual concentrations are relatively small, everything that metals do are amplified. It's the opposite of e pluribus unum; in this case out of one comes many. One metal can actually amplify, and turn over, and catalyze many, many reactions in parallel. I think that we feel like from first principles is a good place to start, because everything you study is not a one-to-one correspondence. It could be a one to a hundred, one to a thousand, one to a million sort of amplification. I think that there are great opportunities to study some elements that will be able to amplify function in that way.

ZIERLER: Is neuroscience your entrée to the adjunct professorship at UCSF?

CHANG: No. It was my general interest in imaging. We talked to people in radiology. We started collaborations to, as I said, translate some of our imaging technologies that we were doing for cell-based imaging over the first five years or so of my career at Berkeley, and then taking those to PET imaging, radio imaging that you could do in mouse models, and then hopefully to people. We've also done some MRI over the years of making new types of functional MRI contrast agents as well. So that was the first direction. Then it grew into our work in chemoproteomics and drug discovery, and some strong collaborations with researchers over at UCSF on that front.

ZIERLER: Chris, a funding question. The affiliation with Berkeley Lab, does that provide or does that optimize DOE funding for you?

CHANG: Yep. Like me and many other people, it is a core program that is funded directly by the US government for doing National Lab research, yes.

ZIERLER: Then for the health research, are you more of a—I don't know what the right word is—a civilian? You don't have that insight connection—

CHANG: Exactly.

ZIERLER: —like you would at Berkeley Lab?

CHANG: Exactly, yep, and so a combination of federal funding, industry support, philanthropy, and so it's a broad base.

ZIERLER: That's a great opportunity to reflect on. You mentioned the three, you know, this is what they are. There's the philanthropy. There's industry. There's government. What does each do well in terms of their motivations, in terms of their timescale, even their patience, even their expectations?

CHANG: So I think federal funding is important, because that is something that's sustainable. It's not just creation of knowledge but also federal funding. There's a support for training the next generation of scientists. The National Institutes of Health, they want to talk about increasing participation in the biomedical workforce. There are many, many different types of career paths that will contribute positively. I think it's something like for every dollar that you put into the NIH, the economy gets $8 back. When you think about taxpayer money going to that, there's nothing that will give you an eight to one ratio of return. I think that that's a really important part. But because the Government moves so slowly, that's where philanthropy really helps. But there are only so many people that have the means to be able to support science research technology in that way. It's not as widely available, I would say, but it has the advantages of speed, focus, and flexibility, because it's not this large governmental operation. Then the third pillar is industry. Industry really is where you translate things to products. It's twofold, in my opinion, because the products are the actual sort of, say, if it's a pharmaceutical company, it's medicines. But the products are also the people that we train. Close connections do help students get internships, permanent jobs, exposure to different career paths. That is extremely useful to them, because not all students are going to become professors. That's one career path. But I think that that's the reason why my personal philosophy is not just you want to raise as much money just because you want more money, but having these different sources gives you the broadest viewpoint on who are the stakeholders for science, and who benefits from science.

ZIERLER: Chris, the two areas—translational biology and energy sustainability—very ripe for start-ups. Lots of ideas to translate into companies. Have you ever gone down that path? Have you ever considered those opportunities?

CHANG: Considered those opportunities, but we haven't really gone in that way. I'm much more, I would say, an academic and a teacher. But we have a lot of intellectual property that we've generated that's been licensed. Some of our reagents are sold as commercial products. Others have been brought into research programs and different industry to help facilitate internal projects. There's been reasonable monetary value for that IP. But I myself haven't really founded any companies. Most of the students and postdocs in the laboratory have not gone down the entrepreneurial path, I would say, so it's really driven by the people that have been trained.

ZIERLER: Is that more of a bandwidth issue on your part, or you really don't have much interest in business yourself?

CHANG: No. Right now, it's definitely a bandwidth issue. [laugh]

ZIERLER: That's not going to get any better probably? [laugh]

CHANG: I don't know. You never know. With a move, bandwidth changes, so I would never say never to anything. But, for now, I think it's a pretty full-time job. It's a big undergraduate institution, lots of teaching, lots of service for such a large organization, in addition to the research that we're doing. We'll experience the big public school and the small private school, we'll compare and contrast, and do the experiment.

ZIERLER: Chris, you mentioned teaching. This is something that you've been recognized for, your commitment to teaching, to mentorship. Let's go first on the undergraduate side. What are the most meaningful classes for you to teach undergraduates?

CHANG: It was great timing for me because when I arrived at Berkeley, they launched the chemical biology undergraduate major. It was the first in the country. Berkeley being a flagship public institution, as well as one with a really large population, we hit the ground running. What I did is I designed this course from scratch. That was the inorganic chemistry requirement for that major. That's been my favorite class to teach over the years. That's something where there have been thousands of students that have gone through that course. It's been really rewarding. I also teach organic chemistry laboratory courses, mainly. I've done some biochemistry. For graduate courses, it's more specialized topics that I've taught—inorganic spectroscopy, bioorganic chemistry, metal signaling, redox biology, etc.—so a lot of courses over the years. When you're a professor for 20 years, you don't want to teach the same thing every year.

ZIERLER: That's right.

CHANG: We need to recharge as well.

ZIERLER: I can't help but ask, launching the chemical biology program for undergraduates, where is Pete Schultz in this story?

CHANG: This was really post Schultz. It really started, I would say, more with Carolyn Bertozzi and Michael Marletta with graduate education, and then it was a collective of different people. Pete is definitely one of my heroes, one of the early people in chemical biology, and his work really expanded the genetic code. We knew him, you know, and he was famous when we were undergraduates, because he was a Caltech product as well. But I think that I arrived at Berkeley probably like eight years later or something like that after Pete left for Scripps.

ZIERLER: Then on the under—

CHANG: We overlapped.

ZIERLER: On the undergraduate side, we were talking about the rise of computational biology. These are now students who grew up with computers. They have such great facility with computers and algorithms. How does that change what they're interested in, and what they want to pursue for careers?

CHANG: I think that what it comes down to is data. They're much better at handling large amounts of data, but they're also better at extrapolating from limited experimental data to make models. I think that the great part about research is that it used to take so long to do certain experiments, but now, especially with imaging proteomics, you're getting large amounts of data. You can get much more out of the analysis through computational power than you ever could before. Before, we're getting binary answers: yes/no; go/no go. But now you're actually starting to see, I would say, mosaic patterns and things that we can't physically see. But if you know how to use computation, then things start to make sense.

ZIERLER: In the way that Harry Gray provided this incredible opportunity for you, are undergraduates knocking on your door? Are you making sure to make room for them in your lab?

CHANG: Yeah. It's been an important aspect. We've had almost 100 undergraduates with mentored research experiences with us, with probably another 50, almost 50 visiting scholars from all over the world. I think providing that opportunity, that first taste of open-ended research and science is very personally important to me because, as I said, it just takes one person to give you a chance. The great part about Berkeley is that there are just so many talented undergraduates that we're usually just oversubscribed, because you do have to provide the mentoring environment for them. You want to provide as many as you can in terms of spots, but they still have to be quality spots for them to get a layered mentoring experience.

ZIERLER: You're saying it does no one any favors by just accepting somebody, and not giving them anything to work with?

CHANG: Yes.

The Unique Business Model of Academic Science

ZIERLER: Chris, graduate side, 20 years of graduate students from your very first to who you have now, who's coming with you to Princeton, just some overall questions about what has changed and what has stayed the same from the kinds of programs, undergraduate programs your graduate students are coming from, their skills, the kinds of jobs that they want to take, the kinds of jobs that are available to them upon graduating, what's changed, what's been constant over the years?

CHANG: I guess I would say the thing that's been constant is that there's just so much talent and passion for doing great science. I think that's something that's been reinvigorating year after year. I think that's one thing that I didn't quite appreciate when I was starting out, because you're not much older than a graduate student when you're a young professor, and you think, in some ways, it's going to last forever. But you do get renewed, where you have people coming and going. I like to say that professors are basically the worst businesspeople, as we make no money because whatever we bring in, we spend it all, if we're doing research efficiently. And we have zero employee retention, if it works out. [laugh]

ZIERLER: [laugh]

CHANG: What sort of position is not making any money with zero employee retention? But I think the products that are produced are the people. That's been constant. At these great institutions, you always have young, excited people, and you're just at this early career stage. I think that's been the same. I think what's been different is that students are much more sophisticated than they used to be. The speed of information, especially the ability of students to communicate with each other, it's so much faster, and so therefore they see the world in a bigger sort of place. They know more about the career paths that they can take. I find them to be in general more sophisticated and focused on the next step, as opposed to when I was first starting, where there was very little talk of what do you want to do after your PhD? For me, I was like, "I don't know. I just like science, and I'm going to do this. I want to take this one step at a time." It can be a double-edged sword. Planning ahead is good, but sometimes you want to be in the moment. I think it's that the information and decision fatigue is real, where there's just a lot more input of information that students have now that they have to deal with.

ZIERLER: Your appointment at Berkeley Lab, is becoming a staff scientist in a National Laboratory, is that a viable option for graduate students coming out of your lab?

CHANG: Oh yeah, and it's a great option, and many of them want to do it. If you live in a place like the Bay Area, the Bay Area itself becomes an ecosystem of tons and tons of different jobs. A very prized one will be to be a staff scientist at the National Lab. It's a great place to work and live.

ZIERLER: There used to be a binary that industry was not a place to pursue basic science, except for a place like Bell Labs, which obviously doesn't exist anymore. Now we're seeing that this is possible, whether it's a Google, some biotech. I wonder if you can reflect on what you're hearing from students who have gone into industry but want to retain a basic science and an even independent research agenda?

CHANG: I think that's where the sophistication of the students is coming online, because you could be someone that would be a founder of a biotech start-up. You get the business on-the-job training at the same time as driving science that, in general, they created themselves as graduate students, or you can go straight to a larger sort of industrial position. They're scientist positions, but they're also ones that are postdoctoral that are meant directly for academic research and publications as being, I would say, the metric for success. Then National Labs are the same way. Then some people want more schooling. They want to get involved in patent law. They want to get involved in different types of consulting or go more on, you know, other sort of not National Lab but state and local government as well. I have a student that just went to the California Energy Commission.

ZIERLER: We've talked about biotechnology. We haven't really talked about Silicon Valley. Have you pursued partnerships with the big tech firms that are interested both in human health and in sustainability?

CHANG: Not directly. I would say that we're still more aligned with industries that are in the biotech sector at this point. I've had several students go into start-ups that are energy-based start-ups, and jumped around from place to place. I think that those are most of the sort of connections. But we, as a laboratory, we haven't collaborated directly with Silicon Valley folk.

ZIERLER: Are the Googles and the Intels of the world, are they thinking about things like artificial photosynthesis?

CHANG: Oh yeah. I would say that everybody is looking to lower their carbon footprint. I think that it's also geared towards being more efficient, and research, and using AI and machine learning as a tool. If it's a needle in a haystack, you want to find the needle sooner. You don't want to dig through the entire haystack. It's a question of where can you find the localized places to increase your probability? I think that that's where these companies are headed towards. For example, a catalytic reaction you want to optimize, then this is the power of it, as opposed to before this, the high throughput screening was thought to be the way to go about it. Where if you can screen really quickly, that will be good, but if you're not looking in the right place, diversity in the screen is most important.

ZIERLER: The one area we haven't covered for graduate students is, of course, those who want to go onto academia. Reflecting on your own experiences as a junior professor to what you're seeing from your graduate students and postdocs who have taken academic positions, what's harder now even than 20 years ago about starting up as a professor? Where are the pressures even bigger than when you began?

CHANG: I would say the biggest pressure is funding. I think that research has become more expensive, in a lot of ways good, because the personnel costs, stipends, tuition have gone up over the years. Stipend, I think, is a really good thing, but it still means someone has to pay for it. The National Institutes of Health, it's had a flat budget since 2000. If you adjust for inflation, it's nowhere near the same buying power. Then if the stipends have gone up, then there are fewer opportunities for people to be educated and supported on those same size of funds. At least for me, I've heard from a lot of early career investigators that funding is a pressure. It's always a pressure, but I think it's more of a pressure than it was 20 years ago.

ZIERLER: What about service work? What's the right blend for junior professors to take on administrative responsibilities while also not overburdening them, because that's not what they're there fundamentally to do?

CHANG: We, in general, I think like most universities, try to minimize the service requirements especially, when you think about it, these are people that are pre-tenure, and so they haven't been guaranteed a job. Therefore, I don't think it's fair for them to have to participate in the service and running of the university until that mutual commitment has been made to them, philosophically. I think that the service is meant to get them integrated in the community rather than fulfilling a duty or responsibility. It's to show them that this is the way things work and that this is how we're all working together. I think that the point of service for a junior professor, early career professor is the community.

ZIERLER: Chris, moving the conversation closer to the present, when COVID hit, did you see an opportunity to get involved in virology and vaccine research?

CHANG: We did, but I think that we were looking at copper as antivirals, and trying to understand basic aspects of that.

ZIERLER: What does that mean, copper as an antiviral?

CHANG: It's also an antibacterial. If you go back to old days, copper jewelry, copper silverware, and copper cups, all of that you would use to store water and wear and eat, and it would stay uninfected. It would be clean. Now we know that it's both a surface antiviral and antibacterial. You can dope in copper or silver into a drinking fountain at a hospital, and it's much cleaner—door handles, etc. That's something that we involved with some of the basic mechanisms of how those could be used. But obviously in terms of therapeutics, the vaccines, and antivirals that are more broad spectrum, that's the applied. But these sorts of ancient remedies are interesting.

ZIERLER: Is that at all relevant for mRNA technology?

CHANG: I would say that you use these in combination. If you have broad spectrum antivirals, you can probably potentiate that with changes in metal nutrients as well. Some people might be predisposed to having, say, a low copper, low iron diet, or a distribution that could help or hurt them if they're taking antivirals or antibiotics, depending on the disease.

ZIERLER: Administratively, was this research enough to allow you to keep your lab open in a way that if you weren't doing COVID research, you had to shut down in most cases?

CHANG: No. We shut down completely for three and a half months for wet lab work. Then we went into shift work, like many groups across the country. We did not do anything special during the COVID time. Most of the COVID time was making sure that the morale of the laboratory was good. We came through it really well. We had a lot of virtual group dinners, things of that sort, which was really nice. A lot of things you could get delivered, and everyone would bake their own pizza [laugh] together or make their own noodles. Those things are actually weird in 20-20 hindsight. But at the time, it was like the only way that people could see each other.

ZIERLER: The forced experiment of shutting down the lab—obviously a wet lab, you have to just stop dead in your tracks—was there opportunity to just step back, and is this a good time for data analysis, for writing deeper papers? Is there any remote kind of automated research that you can do? What were your options during this time?

CHANG: We had a backlog of research papers to write up, and I think that one thing we did was it gave people time to sit down and write. At the very beginning of that time, we were a lot more productive in terms of the paper output, because we had time to sit and to think about things. Then in terms of data analysis, I think that it did move us towards using more core facilities, where we could mail samples out, and then work more on the data analysis, as opposed to doing things locally ourselves. Because we weren't paying for supplies then, you were paying for people to do sequencing for you, or paying for animal breeding, things of that sort, to make mouse models that you would've done yourself. Some of that's been interesting, because team sizes can also vary, and then team compositions can also vary. I think that, for us, we did actually pivot to do things that were more biological, because there was, in terms of density of people that was needed, was not as much.

ZIERLER: You mention the importance of morale. For graduate students who were living on their own, especially for international students who are truly isolated, how did you lend a helping hand remotely during this period?

CHANG: We met regularly, both one-on-one as well as the full group, by Zoom, so no one was alone or didn't have human contact for days. You had to do most things through screens. Then later on, because the weather was good, we were able to do things outside for most of the rest of that year, with distancing. I think that those are intrinsic advantages [laugh] of a warm weather place. But I think it's the combination of meeting people one-on-one, and then having them in group settings as well. We tried all sorts of things, not just a normal Zoom but like this online Gather program, which is like a Super Mario Bros. game.

ZIERLER: Oh yeah.

CHANG: [laugh] That was okay. That wasn't so, so bad with a group of 20 people or so. Then other people, they were still able to go play tennis together, things of that sort where it was low density in terms of the number of people.

ZIERLER: Going back to a question about personal identity, and what you had discovered about yourself coming back to California, during COVID, of course, this was a dark time for how Asian-Americans felt, and the damaging rhetoric that came from the news media, even unfortunately from the government, including the President. What did you learn about yourself and the country during this time?

CHANG: It did, to be honest, take me back to growing up, because I thought about it in terms of like there is always someone who's the other. But, at the same time, it was odd because people were so isolated, it didn't really make that much of an impact on me, because we just didn't see that many people. [laugh] If you don't doom scroll too much then I would say that—but we also were lucky to live in an area of the country which was not as polarized. I would say the Bay Area was quite compliant with a lot of things like masking and high vaccine uptake. In that way, the homogeneous population of people made it much better in the pandemic beginning times than others. But it's still hurtful. It's definitely hurtful. People are people. It does show you that it can turn; it can definitely turn on a dime. What's happening right now with the Middle East shows you another example. It goes to the next thing.

ZIERLER: Was the diversity and equity and inclusivity infrastructure at Berkeley, was it a positive resource for lowering the temperature of some of these tensions?

CHANG: I do think so. Also, as I said, because compliance with health regulations was a big one, I think that the campus did a very good job with really paying attention to people's health in that way. It's more challenging now, I would say, that it's just a high density of people. But during that time, I think that they did a very good job of making good policies.

A Time for Change Post Pandemic

ZIERLER: Chris, of course, the pandemic was an unmooring experience for a lot of people, thinking about what they were doing and where they were doing it. Was this the origins of you thinking that you might move a professorship at some point?

CHANG: To be honest, yeah, it did. It was one of the contributing factors. I think realizing that some of the work could be done remotely, and then connecting with people faster all over the world, I think, made us all feel a little bit less rooted in the physical building as opposed to the people. In a lot of ways, the silver lining is I've been able to connect a lot more with people that are outside Berkeley, because we can do these sorts of things that we would not be doing. It'd be a phone call. It's not the same as this sort of conversation. For me, it was almost like having a mini sabbatical, like, not a good sabbatical though.

ZIERLER: Right. [laugh]

CHANG: [laugh] But knowing that the lab was OK, people were OK, and that you could be away, and so it does sort of, you know, you think about, OK, you've been doing something for 20 years. There's a lot more time left in a professor's life. It's like, oh, why don't we try the experiment, and do it all over again? What would you do differently? What would you do in a place which is the polar opposite of what you're used to, and very happy with? But I think that the pandemic did make people reflect in different ways and, for us, thinking about not having to physically be in this location to do the science and meet new people, to interact with them.

ZIERLER: All of the relationships that you've built, all the research that you've done across campus, across the Bay Area, the power of inertia, to just keep on doing it, why did you overcome all of that when you started to seriously consider the offer from Princeton?

CHANG: As I said, it's stage in life where it was ripe for a change. We had a pause during the pandemic. But then also being married to another professor here, it's a two-professor household. Our daughter is 8 years old, so we have one child. To move at this time, it's flexible.

ZIERLER: Better now than in high school?

CHANG: Moving later is not flexible. A lot of things came together at the same time, and it was kind of a heart-wrenching decision, to be honest. I think that some people are still super shocked that this is occurring. Sometimes, existentially, I'm not sure if, you know, it's like a meta thing. Am I actually in a simulation doing this experiment, or am I going to wake up, and it was like, oh, it was a dream, and I've been here the whole time?

ZIERLER: When you're freezing in February next year, you'll know that it's a reality. [laugh]

CHANG: Yeah. The weather is luckily not as cold as Boston. We've been out a few times. But it's a different area. I think having this sort of Philly-New York nexus, it's just a different type of hub. There's the Boston hub. There's this New York-Philly hub, Mid-Atlantic. There's D.C. Then you've got the Bay Area. Then you've got LA. Then you've got San Diego. Those are, I think, on the coasts, the major centers of higher education, in a lot of ways.

ZIERLER: Do you have collaborators or colleagues on the faculty at Princeton who have given you an insider's view of what makes Princeton special, what you'll be able to accomplish there?

CHANG: Yeah. I think the thing is it's super exciting, and I think it's the trajectory of Princeton as a university as well as chemistry in particular. Michelle and I, we are two of eight new professors that they've hired in the past 12 months.

ZIERLER: All senior?

CHANG: A mixture. It's a mixture of junior and senior. It reminds me again of the way it was 20 years ago at Berkeley when you have this big flux of brand-new people, and I feel that there's an excitement associated with it of the new blood, so to speak. That's something that's really exciting is a bunch of new people. Then the other thing that's exciting is to try an environment again where you could get to know people across campus. Then, as I said, the proximity to two, not just one, UCSF, but two big medical communities in Philly and New York, I think gives us a—it's just a different opportunity for us right now. Then the local industry, my wife is much more tied into the pharmaceutical industry and biocatalysis, and so it's attractive for her as well. It's a great place to raise a family, despite the weather. It's a small town of 25,000. There's one middle school, one high school, and I think it brings me full circle to being more of a small-town person in my upbringing. There were a lot of things that were attractive about it. We do love being here, so anything that we could do to support or add value to Berkeley, and the same thing with Caltech. That makes me smile when I think of these sorts of places that I've been lucky enough to be at.

All About the Pursuit of Knowledge

ZIERLER: Now that we're peering into next steps for you, for the last part of our talk, I'd like to ask a few retrospective questions, and then we'll end looking to the future. Having a hand both in the fundamental research and the translation, I wonder if you can talk about the satisfactions of each, the satisfactions of discovery for its own sake, and the satisfactions of a breakthrough that has tangible societal impact? What does each mean for you?

CHANG: I would say pursuit of knowledge. I think it's really satisfying to, as I said, see something, to be the first one to see something that no other person has recognized, and you're doing it together, because professors, we do it with research groups, we do it with students, and so we're always constantly learning. I think there's just something that will always be exciting about that, and so that type of open-ended question and answer and that sort of cycle. But I think that as you move on in a career, you do want something to give back, and it be something that is of benefit to society. I think that having one foot into new knowledge for its own sake is important, and then having that knowledge be used for responsible purposes, that could help others, I think that that's very rewarding. It really is all about the people. In the end, a professor is a teacher, first and foremost. As I said, our core business skills of having zero retention [laugh], I think that of the people you work with, it's actually the best thing, because you watch them, and it's almost like you're [audio dropped out].

ZIERLER: The last thing I heard was, it's almost like your—you were talking about the students.

CHANG: Oh yeah. I was saying it's almost like a cat with nine lives but, in the end, a professor gets to live many, many more lives than that. I was saying I've had about 200 students that have trained in the laboratory, and thousands that have gone through the classroom. I think watching their journeys and growth and what they do afterwards, that's incredibly rewarding. Whether they do basic science or they translate something into a product, it really is something that helps. It helps society by helping people.

ZIERLER: Chris, you've been honored and awarded in many more ways than we can cover in our remaining time together. But I want to ask a specific question about the sociology of scientific awards and recognitions. Are there any that stick out in your memory that are satisfying, not just because it's great to get recognized but because either in the connections that it makes or in the heads that it might turn, actually amplify the science that you're able to do?

CHANG: I would say that I'm definitely proud of the teaching award at Berkeley, just because I think that was all of the sciences across campus. It showed that it was not just performance in the classroom but new curriculum development. We launched a new major. There have been thousands and thousands of students that have gone through this major, and I think it's changed education to show that chemistry and chemical biology are linked. They're connected. I think that that's had a pretty big impact beyond undergraduate to graduate education as well. I would say that's nice, even though I guess it's a local but not national or international scale thing, where most people would say that, oh, that latter recognition is more visible. But I think that being able to reach that many students at a place like UC Berkeley, with the breadth of the students, the depth of them, and the sheer number, you're impacting a lot of people; more than if you win some ACS award, and you give a nice talk at a banquet. It's nice to be recognized by your peers, but they're really recognizing the students that are in the laboratory as opposed to, I think, a teaching award that actually is about the students that were educated through that process.

ZIERLER: It shows where your priorities are too, obviously.

CHANG: Mm-hmm.

ZIERLER: Finally, Chris, last question, looking to the future. You've already indicated your openness to a variety of new research, new possible industry connections at Princeton. What about two areas we haven't covered, your openness for academic administration, or even the obvious policy ramifications of your academic expertise, both in biotechnology and in sustainability? Are these areas where you might consider going into at the more senior parts of your academic career?

CHANG: I guess what I say is at Berkeley, I've actually done a huge amount of administrative work already. [laugh] I've led the chemical biology graduate program, and our T32 for almost 12 years now, and so a big hand in graduate education. I've served vice chair for our department, as well as on the full campus committee. It's like the equivalent of our Supreme Court [laugh], where it's like all appointments, promotion, tenure retentions were all through that committee. There was only nine of us, and so I've served at that level as well. Maybe not as many front-facing things but things I think that keep the gears of the university running. Moving to Princeton, I think that I'll probably take a step back, and start with research and teaching first, and then see what happens. I feel like you want to learn about a place to see where best you can contribute. I think I wouldn't be so, I guess, egotistical to think that I would know best of how to run something in a place that I've never been at before. I guess that's the way I would think about it. I would obviously be happy to help any place that I'm at get better, and add value to that. But I think that, at the very beginning, I'd like to learn more about the place and what it needs first.

ZIERLER: Then what about—just as an addendum on that—being a short train ride from Washington, D.C.? Is that something that you're interested in as well?

CHANG: Probably not at this point, to be honest. I think that government is one pillar of the scientific process. Right now, I think that I'm looking more locally in terms of what we can do first. Because if you want to go to Washington, I think that you have to have a specific advocacy. I think that there are people that are better placed to do such things right now.

ZIERLER: It's all about the research and the teaching? This is almost like going back to an earlier part of your career at this stage?

CHANG: A little bit, I would say, maybe. But then in five years, we have another conversation if I'm department chair. [laugh]

ZIERLER: [laugh] We'll have to check in. Chris, I want to thank you so much for spending this time. It's been a terrific conversation. I'm most appreciative.

CHANG: Oh, great. Thanks.

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