Professor Betül Kaçar was born in Istanbul, Turkey, and completed her Ph.D. in Biomolecular Chemistry at Emory University and postdoctoral studies at Harvard University and the NASA Astrobiology Institute. After starting her lab at the University of Arizona Departments of Molecular Biology and of Astronomy, she moved to the Department of Bacteriology at the University of Wisconsin in Madison, where she directs MUSE, a NASA-funded research center on early life and evolution, and co-directs the NASA Research Coordination Network on Early Cellular Evolution: LIFE. Dr. Kaçar combines molecular and evolutionary biology with planetary sciences and explores the origins, evolution, and future of life on Earth and beyond. She has won many awards, and her work has been extensively featured by the lay and popular science media.
Chuck Sanders: Hi Betül! We first met a number of years ago when you were a graduate student at Emory and you invited me to visit and deliver a student-sponsored lecture. That was a really fun visit. As I recall you were doing mechanistic metalloenzymology in the lab of Dale Edmondson, who I liked and respected from serving with him on an NIH study section. I then lost track of your career progress till we met again at the 2023 Protein Society Symposium in Boston, where you were an invited speaker and gave a fantastic talk on paleoenzymology. After your Ph.D., you went to Harvard University and the NASA Astrobiology Institute, where you worked in the considerable domain of overlap between paleobiology and astrobiology. That is such an interesting training trajectory! Can you tell us a bit more about this phase of your career? What was most challenging and what was most rewarding?
BetülKaçar: Hi! My doctoral research—though it now feels like it belongs to an ancient era—centered on comparative enzymology of amine oxidases in zebrafish with humans. This is when I started thinking about history and whether we study the right systems for the right reasons. As I progressed through my training, my questions grew larger and more complex – much like life itself evolves over time! I began to wonder: Zebrafish have a version of this enzyme that differs from the one in humans. What is the common origin? I began exploring the phylogeny of the enzyme to trace its evolutionary path. It became clear to me that to truly understand an enzyme’s function today, you must look into its past.
This is when I started attending meetings in the biology department, which turned out to be only one floor below my Ph.D. lab. It didn’t take me long to realize a fundamental challenge. First: Much of life’s history and its key innovations have been lost to time. We are left to work with the fragments that remain today. There’s a tendency to view the past as a “failed” state, assuming that evolution drives toward optimization. This isn’t necessarily true. There is a vast, complex history we have yet to fully understand—and we should strive to uncover it. Second: I need to visit this floor more often! Molecular biology needs to engage more deeply with evolutionary biology. To give some context, this was the early 2010s—a time when the utility of phylogenetics or concept of deep time change, let alone techniques like ancestral sequence reconstruction, were far from widely accepted among cell biologists. The dialogue between these two disciplines is stronger today.
This was the moment for me, I knew I wanted to dedicate myself to studying ancient life and evolution. Instead of venturing into ancient rocks, I wanted to study these problems in the laboratory. I realized I needed to develop an experimental system to study ancient life. I applied for a postdoctoral fellowship with NASA’s astrobiology program, which was open to unconventional ideas. I approached them with a radical research proposal: I wanted to create a molecular time machine. Using a process called phylogenic inference, I would reconstruct synthetic ancient proteins, then integrate these resurrected sequences into modern bacterial genomes. I would then subject them to experimental evolution in the laboratory. The ultimate goal would be to determine whether the evolutionary path of an ancient protein could be recreated in a way that aligned with its natural history.
My proposal was accepted. I started my fellowship in 2012, which started an on-going affiliation and collaboration with NASA, followed by Harvard University and eventually my own research laboratory. I am grateful for all the challenges along the way, they shaped how we think today. Many students, lots of collaborators, big questions spanning Earth and life sciences, from early life to life in the universe, everyday curiosity, and a lot of fun!
Chuck: I know that you moved just a few years ago to the University of Wisconsin. I hope you like it there. I have been to Madison a number of times and think it is a wonderful university town (though I do avoid the fried cheese curds!). In preparing for this interview I was delighted to find that your work seems to have resonated in the popular science community. Your work has been featured on PBS and other venues, you’ve given a TED talk, and you have given a number or high visibility interviews. What have you learned from your experiences of engaging with filmmakers, journalists, and the general public that you can share with scientists whose work may eventually attract the same sort of attention as yours?
Betül: First of all, I will assume that was a typo–because you absolutely cannot avoid the cheese curds. It’s practically a law here. Madison is where my work is deepening its roots and reaching its primary audience: the students connecting the dots between deep time, biochemistry, microbiology, geosciences, and evolution. I am incredibly proud of the Early Evolution of Life course I developed here. The class size has been doubling every year, which is both exciting, encouraging–and a little terrifying, in a good way! I find it almost scandalous that we (biological sciences) don’t consistently teach the story of the very origins of biology and the (albeit fragmented) understanding of its history. Geosciences has done a great job at this, yet we still lack the deeper molecular view of how life adapts and responds to planetary shifts. Through both our research and teaching, I want to challenge this oversight and highlight the importance of connecting biology with its evolutionary roots. Understanding where life came from and how it has evolved provides the context for biological sciences writ large and fosters a deeper appreciation for the complexity of life on Earth.
I believe it’s this second point that has resonated with the public. The support I’ve received over the years has been a major source of motivation for me to keep at it, reminding me that our research has impact beyond academic boundaries. I see it as a responsibility to communicate our work, and I believe the public values the efforts I’ve put into doing so.
One of my proudest moments was presenting on the future for women and girls in science to the UN Commission on the Status of Women during the pandemic. Discussing how disasters disproportionately affect girls’ access to education was personal to me, as I was once one of those girls whose life was transformed by a summer undergraduate research program, an opportunity made possible only because the necessary resources were available (thanks to the support through HHMI). This experience, among others, reinforced my belief that our work should transcend borders. We should actively educate ourselves on how to communicate and engage with the broader community and it is always better to build these skills sooner than later.
Chuck: When I was growing up, one of the things that attracted me to science came from front-yard astronomy with my Sears 3-inch lens refracting telescope. I was especially bewitched by the realization that when you look at the stars, you are literally looking into the past. Indeed, the new James Webb telescope has provided us with a direct view of galaxies just after the Big Bang, over 13 billion years ago! Your work to uncover the primordial biochemistry of early forms of life on earth also involves an attempt to look deeply into the past. Does it sometime give you the shivers?
Betül: Absolutely! We are now able to see further and more clearly than ever before, explore planets in and beyond our solar system, and even bring samples back to Earth. In the coming two decades, we’ll be faced with an overwhelming amount of data, and the real challenge will be making sense of what it all means. I lead a NASA-funded astrobiology research initiative, a five-year project connecting multiple institutions and disciplines to tackle with this very challenge. Our focus is metals–specifically, how geochemical shifts in the elemental composition of ancient oceans may have influenced the evolution of ancient metalloenzymes and proteins. We span an approximately 2-billion-year time frame, from the last universal common ancestor to the emergence of Eukaryotes. Believe me, when a chemist, a biologist, and a geologist walk into a room, it’s not the setup for a joke–its the only way we will ever make sense of this floating blue walnut we call home.
As biochemists and molecular biologists, we work at the tiniest scale—examining the intricate details of molecules and enzymes. Yet, when searching for signs of life on a planetary level, we operate at the largest scale imaginable. This creates a unique challenge: bridging these vastly different scales. The connection lies in identifying universal principles—patterns, processes, and signatures that persist across scales—allowing us to translate molecular insights into planetary contexts and vice versa. It’s a puzzle that requires integrating disciplines and thinking across boundaries. The future belongs to those who can reliably cross these boundaries, but doing so requires thorough preparation. In other words, the key to success in interdisciplinary science is achieving a depth of understanding that matches the original discipline from which a concept is borrowed. This is the ideal, though it doesn’t always succeed in practice. Still, the future belongs to those who make it so.
Chuck: I read your fabulous 2024 Annual Reviews in Microbiology paper, Reconstruction Early Microbial Life. One of the things that I found really interesting about research into the molecular biology of ancient forms of life is the importance of the availability of very old rocks from which isotopic signatures can be obtained that inform on the nature of ancient biomolecules and their biosynthetic pathways. I gather that a major limitation to our current ability to probe the earliest forms of life is that there are virtually no rocks available that are as old as the earliest forms of life on earth. Do I have this right? If so, do you think there will ultimately be ways of working through or around this deficit so that we can get a direct chemical readout on the nature of the earliest forms of life?
Betül: This gets back to the disciplinary boundary I highlighted above–and thanks for sharing my paper! Indeed, the breath you just took, and every breath you take in your entire life, wouldn’t have happened without an event that occurred about 2 billion years ago between two very small bugs. A small microbe took up residence in another microbe, an archaeon. The bacterium respired the oxygen on behalf of the archaeon, providing energy in exchange for food. This sharing of their metabolic resources led to the first eukaryotes. So, when you look out a window, every single thing you can see, everything that is familiar, all plants and trees, all the animals and bugs, everything, they all exist because of a few basic, foundational relationships that were established over a billion years ago. And yet, we have no idea how idea how these events occurred. They are so rare and special, that we call these events ‘singularities’. These biological events appear to have happened once, AND ONLY ONCE, interspersed by vast distances of time and space, and to have no obvious equal, parallel, or contemporary. There are no other survivors from these events to tell a tale of competition, victory, and loss. We know of these singularities because they only have a single surviving example, each of which came to completely reshape our planet for every day that followed. Even in the billions of days that followed, more complex life co-opted and built upon these super survivors, they grew from them; but they did not replicate or exceed them.
I hope the Annual Reviews article does a good job getting to the bottom of the problem. Rocks provide the overall chemical and biological picture of early Earth. Contemporary sequences on the other hand, with careful design, may allow us to extrapolate the roots of early life. (For a good example, see this recent reconstruction of LUCA (Moody et al. Nature Eco Evo 2024)). So, the primary understanding of ancient life comes from the geochemical outputs of once living microbes. We ask: Is contemporary biology an effective proxy to interpret the earliest indications of life? Did life function similarly in its deep past? How reasonable is it to use modern biology as a proxy to interpret the past signals of life? In our initial step, we used ancestral sequence reconstruction and ancient DNA engineering to reprogram microbes. Does this approach fully capture the past of an ancient microbe? Not entirely. However, it is a meaningful beginning, and I believe it holds immense potential for future discoveries. The article articulates the foundations of this approach, towards reconstructing ancient metabolisms and biological systems.
Back to your question, because the oldest and most wide-ranging signal of biological activity on our planet is the carbon isotope biosignatures, we started from there. These biosignatures reflect the long term evolution of the microorganism-hosted metabolic machinery responsible for producing deviations in the isotopic compositions of inorganic and organic carbon. We zoomed into another evolutionary singularity–RuBisCO—a key enzyme in the carbon fixation and photosynthesis process and thought to be a key determinant of the carbon isotope biosignature record on Earth. As a postdoc I collaborated with paleontologist and using ancestral sequence reconstruction have reported that changes in the RuBisCO enzyme that are implicated with the Great Oxygenation Event. When I launched my independent laboratory, this was the first system we pursued. We developed an experimental platform to resurrect a Precambrian RubBsCO variant and engineered it into cyanobacteria to investigate the molecular basis of Precambrian biosignatures. This marked the first integration of synthetic biology into paleontology to recreate ancient signs of life. Our experimental systems are crucial not only for understanding life’s limits but also when interpreting biosignatures are essential for robotic life search missions, such as those targeting Mars. Building on this system, we grew our focus towards nitrogen, nitrogenase, and related isotopes as well. Since the evolutionary and molecular drivers of life’s earliest record remain largely unknown, there is still much work ahead, which is a good problem to have!
I envision a new field or subfield, however you think of it, equipped with the tools of bioinformatics, evolutionary cellular biology, and synthetic biology, to revisit the record of life and learn from the past to guide our current and future efforts towards understanding, improving, and safeguarding the only known life in the universe: us! Not only computationally, but also experimentally. Not only to learn from the past, but also to address our critical, upcoming needs, such as the climate change.
Chuck: Speaking of the most ancient forms of life on earth, here is a question I feel compelled to ask as the former president of The Protein Society. Is there now consensus in the paleobiology community that, prior to the emergence of proteins or DNA, life on earth was RNA-based? Or, is this concept still in the realm of being a just a super-compelling hypothesis?
Betül: The study of the origins of life spans a wide spectrum of phenomena, loosely categorized into geochemical, organic chemical, complex polymeric, and bonafide biological or evolutionary realms. However, we currently lack the language and conceptual frameworks to deconstruct these categories in a coherent way. Historically, the RNA world has been the prevailing and most accepted hypothesis. For me, the intriguing question is this: biology leads us to LUCA, but LUCA is not equivalent to the origins of life. This distinction is where the conversation becomes fascinating. With synthetic biology and careful experimental design, the field is beginning to explore and construct plausible pre-LUCA systems. This represents an exciting frontier for biochemistry—not just for life in the universe, but also for biotechnology. There are very promising potential applications of exploring the origins of life. How do different environments give rise to distinct biological systems? For example, this knowledge can be applied to optimize chemical synthesis, improving resources and energy efficiency. It opens the door to innovative uses of chemical compounds, such as for chemical computation. These are big questions that demand a collective, interdisciplinary effort—an all-hands-on-deck approach.
As you hinted, overlapping with your paleobiological and astrobiological interests, is a good swath of environmental biochemistry, with a lot of focus on processes such as methanogenesis and photosynthesis, and carbon fixation. I recently attended a seminar by Professor Karla Neugebauer on her seminal Yale course “Biochemistry and our Changing Climate” and was struck by the overlap of what she teaching in that course and the scope of your own research program. Is climate change a connection to your work that you are able to find the time to get invested in?
The diversity of life is a testament to its ability in overcoming survival challenges in unique ways. I believe history of life provides an unmatched archive of molecular solutions to extreme environmental conditions. We have barely scratched the surface of this knowledge. Honestly, we’re like third graders when it comes to understanding life—let alone its ancient past. But I and others truly believe that by studying the past, we will uncover biologically proven strategies for navigating the uncertainties of our future.
For example, take nitrogen as a case. All life on Earth requires nitrogen to survive. 78 percent of the atmosphere alone is nitrogen, yet humans cannot use it directly. Instead, we obtain the nitrogen we need for our survival through the food we eat. For over 100 years, humans relied on an artificial industrial method, the Haber-Bosch process, to fix nitrogen to biologically usable ammonia, which could then be used to manufacture crop fertilizers. This process constituted a revolution in our ability to unlock nitrogen, and what followed was a global population explosion. About half of the present-day population is sustained by industrial “N-fixation”, generating more than 180 million tons of ammonia annually. By 2050, the global population is expected to increase to nine billion, and with it, up to a 56 percent increase in food demand and up to a 30 percent increase in the population at risk of hunger. We need to respond to this imminent crisis.
We spent the last few years thoroughly updating our understanding of the origins and evolution of N-fixation and nitrogenase. Where did this enzyme come from? It hates O2 now, but it persisted through planetary extremes, including planetary oxidation itself. So, here we are, confronted by yet another “molecular singularity” whose history we know little of. We showed that Mo-dependent nitrogenase is indeed at least 3 billion years old evolving from a protoenzyme resembling maturase and despite its oxygen sensitivity, persisted through planetary extremes, such as the very oxidation of the planet itself. Recent biochemical studies have built up on this through creative experiments. It’s exciting to see that the origins of nitrogenase are now beginning to inform our understanding of its design principles. My lecture at the Protein Society meeting was on this system and the response has been fantastic. I particularly thank the students and colleagues at Villanova University for honoring me with their Silvestri lectureship after attending the PS meeting.
We thus start from here. We have a long way to go. As Galadriel from The Rings of Power wisely says, “Even the smallest person can change the course of the future.” In biochemistry, we can adapt this sentiment: even the smallest protein—perhaps especially the smallest protein—has the power to change, and indeed has changed, the course of the future.
Chuck: If you could hitch a roundtrip ride to Mars, equipped with a microscope and mass spectrometer, would you go? If so and if you don’t mind my asking, what if it was only a one-way trip?
Betül: We all know a one-way ticket can sometimes cost far more than a round trip, in every sense of the wor(l)d!
Chuck: Ha! Thanks Betül!
Betül: Thank you!
Acknowledgments
This interview was originally published in the Protein Society Newsletter. Chuck Sanders is the Vice Dean of the Vanderbilt School of Medicine Basic Sciences and professor of biochemistry.