Looking for the origins of life using synthetic biology: an interview with Betul Kacar
In the interdisciplinary field of engineering life, synthetic biologists team up with experts from different fields. However, pairing synthetic biology with evolutionary biology is less common and rather striking. Dr Betul Kacar, an assistant professor at the University of Arizona, tells us how synthetic biology can be employed to understanding life’s origins, evolution, and possible existence elsewhere in the Universe.
Kostas Vavitsas: Can you tell us about your research journey so far?
Betul Kacar: Only one history of life has been recorded on our planet, but can we reconstruct some of the contributing metabolic factors of this biological past to see whether things might have played out differently? Is life a result of a fluke accident? What is the likelihood of life occurring elsewhere in the Universe? To answer these questions, my laboratory combines computational and experimental tools and travels backwards in evolutionary time in the laboratory. We use modern molecules to unravel how the harsh conditions of our ancient planet shaped life to be the way it is today, and explore the varying roles of chance and necessity in life’s evolution.
I obtained an HHMI summer undergraduate fellowship while I was a college student in in Turkey; this award brought me to the United States at age 19. I spent a summer at Emory University School of Medicine in Atlanta, and I returned to the same place as a graduate student the next year. I was 20 years old, and had just immigrated to the USA. I didn’t have any family members here. Looking back, perhaps I should have been afraid but I wasn’t. The possibility of success was heavier than the thought of failure, which to be honest didn’t even cross my mind. Science gave me a sense of purpose and it was a personal thing for me. I came here to succeed and understand how proteins work, and that was it. I am a woman from the Black Sea region, and we are known to be “gözü kara” (translates from Turkish as an unwise state of fearlessness). I am not afraid of failure. For better or for worse, I am gözü kara.
My PhD studies were very different than what I do right now. I studied the biochemical and biophysical properties of human and zebrafish amine oxidizing enzymes by recombinantly expressing them in yeast. I loved and still love proteins, but I started to inch towards basic questions towards the end of my PhD project. How did proteins function inside living cells? How did they evolve? Would they evolve similarly if life had to repeat itself? How about on another planet? Do proteins exist elsewhere in the Universe? My questions got bigger and bigger. I developed a research proposal that focuses on experimental evolution of ancient proteins in E. coli and applied to the NASA Astrobiology Program that is keenly interested in these same basic questions. My main driver question was to understand whether evolving a resurrected ancestral gene in a modern bacterial genome would repeat this ancient proteins’ evolution in natural history.
During my time at the NASA Astrobiology Institute as a postdoctoral fellow, I developed a system to engineer microbial genomes with synthetic ancient genes. I then moved my laboratory activities to Harvard University and shifted my attention to reconstructing key enzymatic intermediates between biological activity and global geochemical reservoirs throughout the Earth’s deep history. I am currently a tenure track faculty member at the University of Arizona, jointly between the Molecular and Cell Biology and Astronomy Departments. I am also a co-Investigator of the NASA Astrobiology Institute Reliving the Past Team.
The overall goal of my group is to assess the possible environmental impacts of ancient enzymes on global-scale biotic signatures and we do this through engineering organisms that hold key ancient proteins. We are keenly interested in ancient biology and function at the interface of biochemistry, phylogenetics, synthetic biology, experimental evolution and geobiology. We are funded by the NASA Astrobiology Institute, NASA Exobiology and Evolutionary Biology Program, the John Templeton Foundation, as well as the National Science Foundation.
Kostas: We are used to considering synthetic biology as a thing of the future, but you use it to go deep into the past. How does synthetic biology help you answer your research questions?
Betul: How did life emerge, and where did it emerge? Did life originate once, or did it arise repeatedly? These basic questions have been of great interest to humanity for centuries. Yet we don’t know many fundamental aspects of life’s early stages. Biology can be seen as irrelevant, since understanding the origins of biological processes does not necessarily address the origins of life itself but life’s first steps following its emergence. Nonetheless, today we deal with genetic information that is as old as life itself. I think there is room for biologists in origins of life studies. Biologists understand the molecular underpinnings of complex systems and study, in detail, the physiological responses of extant organisms to environmental change and with proper training, can apply the lessons learned to offer clues about life’s first cells.
I aim to provide insights into the biology of the past and then tie this knowledge to our search for life in the universe. A planet free from life today, doesn’t necessary indicate a planet that never hosted life and to understand whether if this was the case, we need to have more than one instance of life to serve as a basis of comparison. Earth’s past provides us alternative scenarios. Travel to about 4 billion years ago, what might greet you is a hot, vigorous planet with giant lava volcanoes, no major continents and lots of meteorite impacts. But we think life, with ecologies different from what is familiar to us today, probably existed back then too. Molecules of these life forms, however, were close to the fundamental molecules of life today.
I use an interdisciplinary approach by building on modern biology, and travel back in the molecular tree of life to reconstruct the past states of currently existing proteins. About 2.5 billion years ago there was a massive increase in oxygen in the Earth’s atmosphere and we infer that these changes were, in part, being driven or governed by protein behavior. I focus on these proteins and study how they may have changed themselves and how in turn this could have changed our environment.
This is where the synthetic biology comes in. I rely on phylogenetic tree reconstructions to infer the evolutionary history of genes and proteins. I reconstruct selected gene sequences from the built trees and characterize the properties of these synthetized ancient proteins in the laboratory either biochemically or by engineering them inside bacterial genomes. For example, we have recently reconstructed ancient Rubisco enzymes and tracked differences in amino acid sequences and structure over phylogenetic time. We found potentially key changes that we think are implicated with the oxidation of the Earth’s atmosphere about 2 billion years ago. We have also made all the trees and sequences that we generated openly available to the community- the repository website can be found at: http://www.phylobot.com/rubisco.v4/. We are currently expanding our efforts to other metabolically significant enzymes. There are very few tools at our disposal to travel back in time, synthetic biology offers an experimental way for this attempt.
Kostas: How well do we really understand proteins, their function, and history? Can you pinpoint on factors or questions that will change the face of the field once resolved?
Betul: I am astounded every time I come across a biology undergraduate student who doesn’t know how old life is. I am not the expert in the history of biology as a discipline, so I am not in a position to thoroughly articulate why such thinking is missing. I think we need to be training scientists who understand protein function and can also think in terms of the geologic timescale, and that this will be essential to understanding how cellular metabolisms and proteins evolved through billions of years of biological evolution. A lot of assumptions are being made about ancient biology. Synthetic systems that resemble ancient biology might offer clues.
Read more: Directed evolution in synthetic biology: an interview with Professor Frances Arnold
Kostas: Do you have any concerns about the field of synthetic biology? Ross Cloney mentioned overhyping…
Betul: You are spot on. Overhype is worrying- synthetic biology is not a panacea for the world’s problems or even for many problems in the biological sciences, and should not be presented as such. But at the same time, I don’t think overhype is the only problem or even the main problem confronting the field. There are many different problems, each pulling in different directions, and the underlying tension is as you might expect pretty complex. For starters, the word ‘design’ is automatically a loaded term for evolutionary biologists, and yet there many constructive and perhaps even necessary roles that design must play in synthetic biology applications to address fundamental evolutionary processes in the laboratory. Natalie Kuldell of BioBuilder has done wonderful work towards filling this gap by making this kind of work and these questions more accessible for classroom curricula and teacher training, and my good colleague Sophia Roosth just wrote an excellent history of the inherent tension between design and fundamental science in the synthetic biology field in her book Synthetic: How Life Got Made.
Another challenge is quality of communication of synthetic biology concepts to other fields and the public. Think about it- we’ve been breeding and selectively altering the genomes of dogs, cats, horses and basically anything you eat that comes from a farm for centuries, and a good portion of the public and many highly educated people still freak out at the phrase Genetically Modified Organism. I don’t mean to plaster over the legitimate concerns for and against GMOs, but just to point out that we crossed what some would think are bright red lines in the modification of organisms way before the steam engine was even invented! This demonstrates a lack of awareness and we are the ones who are responsible for educating the public. I am a big fan of the work carried out by Gingko’s Christina Agapakis towards increasing awareness of the field within the public and among scientists.
Read more: The story of synthetic biology is still being written—don’t leave the women out this time
Kostas: What is the largest professional challenge you had to face/are facing? What is the single most important piece of advice you would give to a PhD student or an early career researcher in your field?
My number one advice: ignore the advice people give you
Betul: Looking back, I think I did pretty much everything that people advised me against doing. So, my number one advice is to ignore the advice people give you. One size doesn’t fit all. Don’t worry about being that person in the room who looks, acts or thinks differently from others. Own it. Being in environments that are not seemingly right for you could allow you to discover what you enjoy. Instead of trying to fit in, discover what you are good at and what you love to do and build your own unique track. Remember, the road is long.
