Currents of Change: Metabolism shaping cell fate and evolution #MetabolismMondays

All the world’s a metabolic dance, early career scientists are leading the way!

Emerging perspectives in metabolism

This week we’ll meet Anna-Lena Vigil, who is a PhD candidate in the Crocker Group, EMBL. From her postbac days in Seattle to her graduate research in Heidelberg, metabolism has remained her throughline: a dynamic system that powers cells, guides their fate, and adapts across contexts, from cancer to development. What drives her is the vastness of unanswered questions — the sense that even well-mapped pathways hold surprises when viewed through the lens of adaptation, evolution, or cell identity. Her first spark came in a college biochemistry class, where she realized metabolism wasn’t just “organic chemistry with a purpose,” but a living system at the heart of biology. That curiosity led her from studying gene regulation in plants to investigating how metabolism drives cancer cell proliferation at the Fred Hutchinson Cancer Center, Seattle. Along the way, she discovered how mentorship and the freedom to explore questions could transform a research career. Now, as a graduate student at EMBL in Heidelberg, Anna explores how metabolic signals guide cell fate decisions during development — and how these processes can adapt and evolve. In this first part of our conversation, Anna reflects on her scientific journey, the questions that drew her in, and why metabolism remains her lens for exploring life’s complexity using Drosophila as a model. In this first part of our conversation, Anna reflects on her scientific journey, the questions that drew her in, and why metabolism remains her lens for exploring life’s complexity. Check out all her work here.

What was your first introduction to the field of metabolism – what’s your first memory?

Outside of learning that the mitochondria is the “pOwErHoUsE” of the cell in high school biology class, my first introduction to metabolism started in my first biochemistry class at the University of Nevada, Las Vegas during my bachelor studies. My professor jokingly described the subject material of his class one day as: “organic chemistry but with a purpose.” During my time in this class, I was fascinated to learn how biological systems have figured out these extremely intricate ways of sustaining life through various different metabolic processes. It was after this class that I knew I wanted to learn more about how biochemical processes that make up metabolism can be the driving force of life on Earth.

Could you share your journey into studying metabolism and what inspired you to specialize in metabolic studies using two incredibly unique systems – mammals/cell lines and flies?

After my undergraduate studies, I was really interested in diversifying my research experiences in the early stages of my career. After studying gene regulation and stress tolerance in plants, and hibernation in a peculiar hibernator during my undergraduate research journey, I was really interested in understanding how metabolism can shape phenotypes, and how it may provide insight to help broaden our knowledge of disease mechanisms. So, with this in mind, and of course a stroke of good luck, I joined Lucas Sullivan’s lab as a research technician at the Fred Hutch Cancer Center in Seattle, where the lab’s main area of focus was understanding metabolic determinants of cancer cell proliferation. It was there where I learned of mechanistic details of how metabolism occurs in real systems, and how it can go wrong to lead to disease phenotypes, such as cancer. I think my drive for understanding metabolic systems really flourished in Lucas’s lab, as he was a great mentor and allowed me the resources and flexibility to pursue my own interests and curiosity. His passion for metabolism was infectious and he had a special way of promoting this same passion within his own lab members. Having a good mentor can really determine the rest of your research career! And after gaining a more informed mechanistic understanding about cancer metabolism, I wanted to learn more about physiological metabolic programs throughout development, so naturally using Drosophila as a model to learn more about this was a good way to transition from cancer metabolism to developmental metabolism.

Tell us about your undergrad/postbac work – particularly about the role of mitochondrial redox adaptations in regulating cellular fitness in the context of both normal and tumor cells.

The work on mitochondrial redox adaptations was an amazing project that was led by Dr. Madeleine Hart, a very talented graduate student in the Sullivan Lab at the time. She was primarily interested in understanding how certain subtypes of cancers, in particular, succinate dehydrogenase (SDH)-deficient cancers, were able to sustain intracellular aspartate when a major mitochondrial protein responsible for generating aspartate, was defective. SDH is also known for its role as complex II in the electron transport chain (ETC) in the mitochondria, and is responsible for the oxidation of succinate to fumarate. Fumarate is then later converted into malate and finally oxaloacetate, which is used to generate aspartate, a key amino acid that is required for cell proliferation. So, understanding how cancers with abnormal ETC activity sustained intracellular aspartate levels gave us an opportunity to learn more about the basic biology driving these types of cancers. In a glimpse into Madeleine’s work, she discovered that SDH-deficient cells were able to adapt to limiting environments by also adapting to downregulate the activity of complex I in the ETC. This downregulation resulted in restoring the NAD+/NADH balance to support further cancer cell proliferation. While we did not investigate this phenomenon in normal cells, the aspects we learned about how cell proliferation can be sustained in these scenarios helped provide insights into the broader theme of cellular adaptation to varying environments, in both normal and disease contexts.

The project I primarily worked on during my time as a technician included discovering novel metabolic fates in NRF2-activated cancers. As we all know that key metabolites and the components of metabolic pathways of cells have been known for decades, there are likely still metabolites, and entire metabolic pathways that are yet to be discovered. This is especially important when we think about how alterations in metabolism can lead to various human diseases. So to tackle the goal of trying to identify novel metabolites, we were interested in finding a system in which unknown metabolites likely existed, and so we decided to turn our attention to NRF2-activated cancers. NRF2 is a main transcription factor that regulates the production of various different antioxidants and detoxification programs. In the process of upregulating these detox mechanisms, one key target gene of NRF2 includes the xCT/SLC7a11 antiporter system, that is responsible for the uptake of extracellular cystine, and the excretion of glutamate. So with this in mind, and with the help of a clever isotope tracing method, we were able to uncover and validate ~9 novel metabolic fates, some of which can be detected in tumors. Also in this work, we learned very interesting aspects of intracellular cystine/cysteine that may help broaden our knowledge of cell proliferation mechanisms and metabolic phenotypes in cancer. I was very grateful to have been able to work on this project with such an amazing team, and hopefully you can read all about it soon!

Tell us how you got interested in cancer/immune metabolism for your post-bac work and how did you transition into Drosophila to study metabolic control of cell fate decisions?

For me, many aspects and fields of scientific research are extremely fascinating, but I decided to pursue metabolic research because I felt as though it viewed biology at the most molecular level in order to understand how life occurs. Many foundational concepts of metabolic programs that we know today were discovered using cancer model systems and in the context of cancer biology, so I felt as though joining a lab that studied cancer metabolism was a great way to enter the field. Although I greatly enjoyed my time working on how metabolism can be rewired to drive diseases, I wanted to learn about metabolic systems more from a normal physiological perspective, for example, in the context of developmental programs. In other words, I wanted to change from understanding how metabolism can go wrong (for a patient) and lead to disease, to learning about all the ways that metabolism can go right and facilitate the development of a whole organism from one single cell.

Metabolism is generally viewed as the sum of biochemical reactions that occur within cells and organisms to provide energy in the form of ATP, with the production of anabolic precursors and maintenance of NAD(P)+/NAD(P)H co-factor pools. A less appreciated view of metabolism is that metabolites themselves can act as signaling molecules to facilitate the up- or downregulation of other cellular processes. As certain cell types become more differentiated, so do their biological roles and needs, which at the root is driven by the utilization of alternative metabolic pathways. As someone who appreciates just how nuanced and complex biology can be, it was reassuring to learn that metabolism is also something that is extremely multifaceted, with new metabolites, roles of metabolites, and metabolic systems that are emerging everyday.

Tell us about your current work and how are you using flies as a model to study physiological consequences of metabolic signaling and its impacts cellular status and development?

My current work is about understanding how mutations in the genome can lead to altered metabolic states, and how these altered metabolic states can be inherited through generations. Mutations are thought to be the driving force of evolution; as mutations in coding regions are thought to affect mature RNAs or protein, noncoding mutations, or cis-regulatory mutations, are thought to affect the levels of transcription, acting as a knob to fine-tune expression programs throughout development. For my PhD work, I am interested in understanding how these mutations can lead to altered metabolic phenotypes, and in particular, how metabolism can be rewired to accommodate adaptive phenotypes, and how these adaptations can persist and lead to evolutionary novelties. These broad questions are especially important when considering natural Drosophila populations that are exposed to various different agrochemicals that are used in modern-day agricultural practices. I am interested in understanding how mutations in regions that are associated with detoxification programs affect adaptive phenotypes in the form of agrochemical resistance. These types of questions can hopefully assist us with understanding resistance mechanisms in natural populations, and how we can potentially use this knowledge to better design more targeted approaches when trying to combat agricultural pest species. Although this specific aim is not super relevant to human disease, learning about resistance mechanisms in general can provide insights into how certain aspects of this mechanism can potentially be conserved to humans and may help provide orthogonal evidence to understanding these mechanisms in general.

Your work intersects metabolism, development and cell biology. How do these fields overlap and how do you integrate these disciplines in your research, and what unique insights have emerged from this approach?

In my view, the field of metabolism is so deeply connected with every aspect of biology that when you think of any phenomenon in a biological system, there is a  metabolic contribution to it. This is especially interesting when considering a developing organism, and how it has figured out methods to perfectly coordinate its metabolic needs in order to facilitate the existence of multiple cell types at once. As every cell type emerges throughout a given developmental program, the metabolic needs of each one of those cell types changes to then carry out more specialized functions. For example, mutations that affect metabolic systems which arise in the germline of a fly may or may not have an immediate impact on certain processes early in development, but then those changes are more apparent when certain cell types become more differentiated and specialized. As my work focuses on how mutations can impact metabolic phenotypes, understanding how these impacts manifest in different developmental stages will provide a more complete picture of the physiological mechanisms at play.

You have worked with both in-vivo and in-vitro systems. Tell us about their roles and how important it is to study both in the context of both normal development and diseases?

In vitro and in vivo systems both have their pros and cons. In my experience, working with in vitro cell culture was an easy way to get a generalized picture of how basic cell biology occurs and what aspects of metabolism are altered in the face of perturbation in the most basic biological level. Also, cell culture is actually very easy, as you just have to split your cells before confluence, switch out media, and freeze the cells when you don’t need them. In vitro systems do allow you to interrogate a disease space without the ethical constraints associated with testing ideas in actual patients, so it is still a very powerful method to test hypotheses about disease mechanisms.

In vivo systems, such as Drosophila, are a bit more difficult to maintain, but also more interesting in the context of multicellularity and development. Flies have longer generation times than cells in a dish, so it could be a few months before you have your transgenic line needed for your experiments. However, Drosophila do provide a very testable platform to study inheritance patterns, the developmental context of specific phenotypes, and metabolic aspects in the context of a whole organism.

Tell us about the experimental approach/techniques you are using for your project.

Luckily for me, Dr. Xueying Li, a previous postdoc in the lab, developed a method which involves fusing transcription factors with a cytosine deaminase domain that induces mutations in proximal regions of specific transcription factor binding sites. This method, termed TF-HighEvolutionary, can be used to induce targeted mutations within networks of interest and can potentially lead to new phenotypic outcomes. My approach involves using this tool in combination with a lab evolution setup, so the hard part will be having to wait a while for cool results to emerge!

Tell us about how you see the future of metabolism evolve with the new upcoming tools.

In my work, I have extensively used various isotope tracing techniques measured by targeted and untargeted liquid chromatography-mass spectrometry (LC-MS), but I think newer techniques that allow you to visualize different metabolites, such as metabolic biosensors or combined spatial assays with cell- or tissue-level resolution, are going to be very useful for the future of metabolic studies.

What are your upcoming plans? What metabolic pathways or signals you aim to investigate further to understand their role in cell fate/cancer progression?

As I worked on the NRF2/antioxidant pathway during my time at the Hutch, I am really interested in investigating this orthologous pathway in Drosophila as well. I am excited to see what physiological aspects of this pathway are conserved, and how it can operate in a non-oncogenic developmental context.

What changes have you seen in the scientific community in regard to studying unique aspects of metabolic signaling in flies?

I think there are many great groups studying many fascinating aspects of metabolic signaling. I really appreciate how the field is moving toward investigating not only specific pathways, but how these pathways are integrated as a system rather than considering them in isolation. I do believe we are moving toward a more nuanced understanding when we consider them on a systems-level and I can’t wait to see what the future holds for the field.

What role does curiosity play in your life, both within and outside of science? What motivates you to be a basic science researcher?

Curiosity is the fuel that keeps all scientists going! Curiosity is crucial to make it through difficult periods that are inherent to science, and I am grateful to have new curiosities to pursue everyday. I think basic science research is the diesel that fuels our societal understanding of the natural world around us. I find it a great honor and privilege to be able to contribute my career to help broaden our collective understanding of how nature works. Knowing that something I observe in the lab may be the first time it has ever been observed is literally the most exciting thing you could experience. To me, there is no better way to spend the day! I believe that basic science questions lay the foundation for the rest of the scientific community to build upon, and aid in advancing our collective health as a society. Without basic science research, the realm of health advances that we have achieved would eventually collapse. Understanding basic principles of how biology occurs in a general sense is the only way we can progress in the fields of health sciences as well, as many basic science and clinical questions overlap. Moreover, I am a huge plant lover and have many plants in my house. I find having plants in my home and seeing all the crazy developmental stages and cell-type changes that occur when you propagate them brings me back to why I find biology so cool!

In the second part of our conversation, Anna reflects on how her training shaped her scientific independence, shares her journey from research in the U.S. to graduate studies in Germany, and discusses how she transitioned — all while holding on to her fascination with the many roles metabolism plays across biology.

Previously we learnt about the role of metabolism in developmental patterning and embryogenesis. Check out – Metabolic Origins: Steering of early developmental fate featuring Kristina Stapornwongkul. Krisitina will be starting her lab at her own lab at IMBA, Vienna and will be hiring soon. Check out her lab page here !

Check out the article All the world’s a metabolic dance, and how early career scientists are leading the way !!

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