BBA Rising Stars announced
We offer our warmest congratulations to the winners of the 2022 BBA Rising Stars Special Issue and Prize
This biennial initiative aims to recognize the accomplishments and promise of researchers in the early stages of their independent careers and draw international attention to the work they are doing.
BBA Rising Stars Special Issue
The BBA Rising Stars Special Issue draws together papers published across each of the BBA journals in one issue. All papers are from researchers within 10 years of completing their PhD (career breaks are taken into account) and have been identified by the Executive Editors of the BBA journals as having the potential to influence future research directions in biochemistry and biophysics.
Alison Donnelly Axtman
Characterizing the role of the dark kinome in neurodegenerative disease – A mini review(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - General Subjects
What are the major themes of research in your group? My interests lie at the interface of chemistry and biology, with an emphasis on using small molecules to explore and impact disease-propagating biological pathways. We focus on understudied proteins with described disease relevance but no potent and selective compounds to explore the associated biology. Understudied proteins are defined as those with few publications describing their role and/or for which the function is still being characterized. Active projects are aimed at finding pre-clinical candidates that address the need for new disease-altering therapeutics in human diseases, especially neurodegenerative disorders. Scientists in my group are working to design and synthesize high-quality chemical tools and develop screening assays to illuminate the function of understudied proteins in health and disease. Our ultimate goal is to deliver potent and selective chemical probes that we openly share without restrictions with the research community.
How and why did you come to work in these areas? I have worked on modulating human proteins, especially human protein kinases, using small molecules throughout my research career with the aim of developing chemical starting points to treat human diseases. The majority of these projects have had strong implications in neuroscience. My research has blurred the interface of chemistry and biology and honed my ability to employ skills from both fields to interrogate disease-propagating pathways. At every stage, I made both potent and selective small molecules and evaluated their biological activity. I continue to characterize novel targets in neurodegeneration using my interdisciplinary skillset. My lab is part of the Structural Genomics Consortium (SGC), which aims to develop target-enabling packages (TEPs) for proteins within the dark proteome. One component of a TEP is a chemical starting point for the protein of interest. Furthermore, the SGC operates in with an open science framework. Thus, my interest in understudied proteins and our open science philosophy are partially rooted in my lab belonging to the SGC.
What do you think has been your most influential work to date and why? Casein kinase 2 (CK2) is a pleiotropic kinase with more than 300 identified substrates. These substrates regulate many disease-propagating pathways. As such, CK2 inhibition has been explored as a therapeutic strategy for multiple indications. While a plethora of papers have been published to characterize the functions of CK2, a high-quality tool to accurately link observed phenotypes with this protein kinase was not available. Furthermore, most studies were executed using suboptimal CK2 inhibitors that lack potency and/or selectivity and confound interpretation of results. I published the design and evaluation of the best available chemical probe targeting CK2 in Cell Chem Biol (doi: 10.1016/j.chembiol.2020.12.013). As part of our study, I used this CK2 chemical probe to demonstrate that, despite its reported links with cancer, potent and selective inhibition of CK2 did not elicit a broad anti-proliferative phenotype. My challenge of the broad cancer essentiality of CK2 that had been the dogma in the field was noticed and spurred several papers in response (doi: 10.1016/j.tips.2021.02.002 and 10.1038/s41420-021-00717-4). As ours is an openly shared chemical probe, it has been used by my group and other groups to investigate the anti-viral (10.1021/acschembio.2c00378), neuroinflammatory (10.3389/fnmol.2022.824956), and insulin regulating (10.3390/pharmaceutics14010019) functions of CK2. Additional studies with this compound are ongoing and will be published in the coming months. The impact of the initial paper, editorial responses, and uptake of the chemical probe in studies support the influential nature of this project.
What do you hope becomes the future of your research? I hope that through my studies I can help validate a new target for a neurodegenerative disease. My lab currently works on characterizing novel protein targets for Alzheimer’s disease and amyotrophic lateral sclerosis. Due to the complexity of these diseases, patients do not currently have efficacious, disease-altering treatment options. The high-quality chemical tools that I develop could be used in pre-clinical studies that provide the basis for clinical trials. Discovery of a therapeutic option that either slows or halts disease progression would be transformative for patients in need.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? My first position after my postdoctoral fellowship was at GlaxoSmithKline (GSK) in Research Triangle Park, North Carolina. Within a year of being hired, GSK decided to close our site. My position was relocated to Pennsylvania. It was at that point that I had to decide whether to move with my job or leave GSK. I ultimately chose to leave industry to help establish the first U.S. site of the Structural Genomics Consortium (SGC) at UNC. Several members of my chemical biology team at GSK made the move to UNC along with me, which helped ease the transition. Still, there were some adjustments to a career as an academician, including the learning curve associated with grantsmanship, but it has been an overall positive experience.
What is one thing you want to say to other researchers in the early stages of their independent careers? I would suggest to early-stage investigators that they collaborate as much as possible. Develop relationships with established investigators that have orthogonal expertise to yours and synergize on projects as a team. Funding agencies love dynamic and interdisciplinary teams of researchers with diverse training and experience. Furthermore, science is more quickly advanced when we work together rather than independently.
What do you see as the future direction of research in your field? The design and development of bifunctional molecules is a future direction in my field. Small molecules engineered to execute divergent post-translational modifications have been exemplified and the portfolio of possible activities keeps growing. This will only be enhanced by the characterization of additional E3 ligase ligands that target and recruit the more than 600 E3 ligases. Furthermore, bifunctional molecules have advanced into the clinic and are well tolerated and effective in humans. The promise of bifunctional molecules has been proven and their potential continues to grow.
Anything else that you’d like to add? Thank you for the opportunity to showcase my research! Please reach out if you would like to collaborate.
Of axons that struggle to make ends meet: Linking axonal bioenergetic failure to programmed axon degeneration(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Bioenergetics
We focus on axon degeneration and how glia interacts with axons during injury and disease. Axons degenerate via active and progressive mechanisms, and we found that glia alters its metabolic state in response to an injury to modulate these mechanisms of axon loss. We study which alterations at the metabolic and molecular level influence the rate of axon loss.
How and why did you come to work in these areas? Axon degeneration occurs in many conditions, ranging from diseases to aging. Altering the rate of axon loss benefits the outcome of many of these conditions. Therefore, axon health is a target of future therapies for improving overall health. At the beginning of my career, I focused solely on axons and their intrinsic cell-autonomous mechanisms, in part because I often studied neurons in a dish. More recently metabolic cell-to-cell communication has begun to emerge as a central theme in neuroscience, and I started to wonder whether other cell types would play a role in axon survival after injury. It has been exciting to discover the role of Schwann cells in this respect.
What do you think has been your most influential work to date and why? Axon degeneration has been the unifying theme of my research since my graduate studies and therefore I made several discoveries along the way that have been influential. The most recent one has shown that Schwann cell metabolism dictates the rate of axon loss and has shifted the attention to the environment outside the neurons. But even before that, I showed that the metabolic enzyme that produces NAD+ works locally in the axons to protect them from injury.
What do you hope becomes the future of your research? I will go in two directions: on one hand I want to discover the basic molecular crosstalk between axons and glia in response to various stimuli. This will answer fundamental biological questions regarding neuron-glia cell communication. On the other hand, I want to explore which steps of this interaction can be modified in a translational way, to ultimately alter the rate of axon loss in patients.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? At the beginning of my career, I have been assigned a mentor who had profound mental health challenges that impacted her ability to do science and to mentor me. It was very difficult for me to navigate the necessity to grow academically while lacking guidance, and at the same time respecting her triggers and conditions. Ultimately, she moved away from the laboratory, and I was able to find other senior members that could guide me in my projects. These events made me aware of the importance of mental health, especially in the academic environment, and have been a reminder in my career to strive to be a good lab citizen.
What is one thing you want to say to other researchers in the early stages of their independent careers? I would like to repeat a great piece of advice that I have received from a brilliant researcher at Washington University in St Louis during my postdoctoral training. I paraphrase here what Professor Raphael Kopan once told me: “there are two kinds of painters: those who paint a piece of artwork and need to write their name on it to feel accomplished, and those who paint a piece of artwork and just admire its beauty, no need for a signature”. Find who you are early in your career and be who you are.
What do you see as the future direction of research in your field? It is becoming clear that axon degeneration cannot be viewed merely as the loss of neuronal projections. A holistic response to injury, involving complex cellular interactions, is emerging as an early event that dictates neuronal survival. Blocking one neuronal pathway only or altering neuronal bioenergetics is likely insufficient to keep neurons alive and functional. Instead, the support system that other cell types afford to neurons once injured will become an area of increased interest.
Anything else that you’d like to add? I am very honoured to receive this BBA Bioenergetics Rising Staraward and thank you for giving me the possibility to speak about myself and my science in this interview.
Defective protein degradation in genetic disorders(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
What are the major themes of research in your group? My lab is interested in understanding the molecular mechanisms that underlie the process of oncoprotein-mediated cell transformation. We are mostly focused on the signal transduction events that occur in cells in the presence of different oncoproteins that can lead to cancer formation. Among many oncoproteins, we think that the RAS family of GTPases embodies the perfect system to study this, because many RAS proteins have been involved as drivers of cancer. Given that the process of transformation is highly complex, we take advantage not only of biochemical and cellular techniques, but we also develop novel mouse models to be able to study the effect of these oncoproteins at the organismal level. More recently, we became particularly interested in oncoproteins that have also been linked to the pathogenesis of genetic disorders or syndromes. We think that we can learn a lot from studying these rare disorders in which the oncoprotein is expressed in different cellular lineages and gives rise to a very different phenotype compared to cancer. In addition, in these monogenic syndromes, the oncoprotein is not associated with other mutations, so they present an ideal model to study the signalling properties and mechanisms of regulation.
How and why did you come to work in these areas? My research interests have been evolving over the years. I originally trained as a pharmacist and started my PhD with the idea of better understanding the molecular vulnerabilities of cancer so that we could develop novel therapies. During my PhD at the laboratory of Dr. Jose Baselga at Memorial Sloan Kettering my research was focused on the PI3K pathway, which is a pro-survival signaling cascade particularly important in some tumors like breast cancer. We studied novel compounds targeting this critical oncoprotein and tried to understand why some tumors were more likely to respond to the therapy while others didn’t or eventually developed drug resistance. I made several discoveries in this context but had the feeling that I needed to understand even more how oncoproteins work. At the same time, I became interested in a group of congenital disorders driven by PI3K, the same pathway that I was studying in cancer, and became fascinated by the fact that the same oncoprotein could cause such different conditions. Therefore, I decided to do my postdoc in a lab with more expertise on biochemical and signaling techniques and joined Dr. Frank McCormick’s group at the University of California San Francisco. There, my research became more mechanistic and focused on different biological questions regarding the RAS GTPases, which had been a major interest of the lab for decades. Taking together all these years of training and learning many different and useful techniques, I am now beginning my independent career at New York University School of Medicine trying to tackle this highly complex biological question.
What do you think has been your most influential work to date and why? I think that probably the most influential project that I have worked to date started while I was working on my PhD studying the role of PI3K in tumor formation. I discovered that the same activating mutations that can drive breast cancer are also responsible for causing a non-cancerous disorder termed venous malformations, which is an abnormal overgrowth of the endothelial cells. Patients with venous malformations do not have many therapeutic options and these lesions can cause severe pain, bleeding, and disfigurement among other morbidities. I was able to develop a mouse model to study this rare disease and demonstrated that these could be treated pharmacologically using PI3K inhibitors, either administered systemically or topically. The reason I believe this work has been quite influential is because, based on these results, we co-founded a company that developed novel topical PI3K inhibitors for patients with venous malformations. That novel drug that we pioneered has recently completed a first-in-human clinical trial, so I had the privilege to witness the life of a novel drug, from the discovery of the disease cause to its development in the clinic.
What do you hope becomes the future of your research? It is very difficult to anticipate the future of my research, because something that I have learned in my career is that research can take you to very different places that you did not foresee. I am interested in studying very fundamental questions, such as the mechanisms by which protein signalling can drive malignant transformation and I hope that over the next years we can make some breakthroughs on some of these mechanisms and pathways. Although I focus mostly on the signalling part, the overall end goal of my research is to eventually apply these unique findings into the discovery of novel therapies. Hence, I am confident that our research can result in identifying new pharmacologic modalities for cancer and other congenital disorders. But most importantly, I hope that our lab’s research also serves as an inspiration for the next generation of scientists and we can attract new talent to our field.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? I think challenge is inherent to the scientific discovery and most projects I have worked with have had some challenges along its course. This might not be evident when you read a scientific paper, because data is presented in an organized manner that appears to follow a linear narrative. However, most of these scientific projects do not follow such linear path and, instead, are full of dead ends and unexpected turns. I think this is exactly what we have trained for as scientists; to be able to find solutions and overcome any barrier in our projects. Although this can be very frustrating at times, it is also what makes science extremely rewarding and exciting when you find the solution! I mentioned before what I consider my most influential work to date, but would you believe that I almost decided not pursuing this project?! The reason is that we found serendipitously that PI3K mutations cause venous malformations in mice, but at the time we thought this was just an artifact of our animal model. It took some curiosity and perseverance to find out what was really happening in those mice, but eventually everything made sense and we got ourselves into a completely new field. It is also extremely important to be in a scientific environment where you are encouraged to take risk in your research and further explore those results that may not make sense a priori.
What is one thing you want to say to other researchers in the early stages of their independent careers? Research, particularly in academia, is highly competitive. Our work is constantly being evaluated in the form of manuscripts, grants, awards, talks, and many others. And as such, we often face many rejections. In addition, our experiments can often be frustrating, because we don’t get a technique to work or we don’t know how to interpret a result. I think it is important to always keep in mind that our worth as scientists can not only be measured by these, so don’t give up! Be persistent and productive with your research, try to find answers to fundamental biological questions that interest you, and it will be recognized by your peers. It’s competitive out there, but we need all types of research; we need your research! Research is also about doing elegant and reproducible science, collaborating with others to move the field forward, mentoring and inspiring the next generation, working towards an inclusive and diverse research community, and many other aspects that will have a tremendous impact in the long term. So, when facing rejection, you can always think about all the other things that you are contributing to and focus on the positives.
What do you see as the future direction of research in your field? I think that signal transduction as a field has been losing popularity over the years. As a result, we are seeing less new labs working exclusively on it. However, I am very convinced that signal transduction is still much needed to understand key biological processes and to develop novel therapies for different pathologies. Thus, I hope to see over the next years a shift towards studying signaling events in more complex biological systems that were considered too complicated in the past; for instance, during the processes of embryogenesis, tumor formation, immune response, neurophysiology, and many others. I think that we have now very good techniques that can be used to measure signaling in these models, such as straightforward and unexpensive genetic editing in the mouse that can allow us to create reporters of specific pathways, mutant proteins, or tagged versions of our protein of interest. I would love to see that the field moves in that direction, our lab is certainly doing so.
Anything else that you’d like to add? In academic research we tend to recognize individuals for their work and achievements; however, these are also the result of many others that have helped and contributed to the career of the awardee. In my case, I have been extremely lucky to have had so many inspirational and supportive mentors and mentees, collaborators, colleagues, and friends. I am very grateful to those that have taught me so much and encourage me every day to continue to do science and think outside of the box. Thank you all!
Felicity M. Davis
Mammary basal cells: Stars of the show(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
What are the major themes of research in your group? My teams are spread across two universities, and we explore quite a few different biological systems, ranging from mammary biology to spermatogenesis. What unites us, is our curiosity to understand how cells decode signals and relay messages to other cells through intra- and inter-cellular calcium signalling.
How and why did you come to work in these areas? I did my PhD on calcium signalling in in vitro models of breast cancer metastasis. Honestly, I picked this PhD for the people, not for the topic. I knew how important good mentorship was going to be at that stage of my career and I suspected that if I were to place my enthusiasm and tenacity in the right environment it would go a long way. It did! When it came time to find postdoctoral topics and laboratories, I decided that this would be a great opportunity for me to challenge myself, both professionally and personally. So I moved to the USA and later to the UK and immersed myself in some related but distinct science. This enabled me to forge a new area of research when I started my own group in 2018, and gave me the space and time to answer some really challenging questions.
What do you think has been your most influential work to date and why? This is a difficult question. I think it is pretty incredible to be able to describe an aspect of physiology or biology for the first time, and I think that the work I did in Jim Putney’s lab at the NIEHS, describing roles for ORAI1 channels in the lactating mammary gland and the testis, is something that I am extremely proud of. In Cambridge, I worked with an incredibly talented postdoc, Bethan Lloyd-Lewis, to perform the first neutral, low density, genetic lineage tracing study in the mammary gland. This was an extremely exciting time in my scientific career. But I think the highlight of my career so far has been bringing these different techniques and expertise together, working alongside some wonderful early-career researchers in my group and creating a system where we can perform volumetric calcium imaging in mammary tissue to explore this biology in a new dimension.
What do you hope becomes the future of your research? When we share our science, we try to do so in a way that is accessible and interesting for non-specialists. I hope that this creates space for other researchers to get interesting in the field of female biology and women’s health. It is time that these aspect of science are prioritized, invested in and openly discussed.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? Honestly, there have been many. Mostly related to issues surrounding equity, diversity an inclusion in the life sciences, and of course these have been amplified since I have started my independent group. I love science, but there are many aspects of the environment in which we practice our science that need to be changed.
What is one thing you want to say to other researchers in the early stages of their independent careers? This is a tricky question because I don’t honestly believe in one-size-fits-all career advice. If I had to say something, I think I would say that it is going to be difficult at times, so to try to enjoy the small victories. And to try to stay curious with your science.
Characterization of large intact protein ions by mass spectrometry: What directions should we follow?(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
What are the major themes of research in your group? My research focuses on the analysis of intact proteins by mass spectrometry, using an approach that is also known as “top-down” - as opposed to the more common “bottom-up” strategy which is based on the analysis of short peptides obtained by enzymatic digestion of the original proteins. More specifically, my research is focused on large proteins, with mass larger than 30,000 Da. In my lab we are designing new methods to characterize these complex biomolecules and prove that it is possible to do so in a high-throughput manner.
How and why did you come to work in these areas? It happened almost by mistake. I had the great opportunity of joining the lab of Dr. Yury Tsybin at EPFL for my graduate studies, but the original plan was not necessarily to work on biologics, because there were also other interesting protein-related projects in the lab. Anyway, I started focusing on intact antibodies, which are very large, multi-chain proteins, and I liked the challenge they posed. So, after obtaining my PhD I continued my journey in top-down mass spectrometry in the lab of Dr. Neil Kelleher. The idea of moving top-down proteomics beyond what in the field we call the “30 kDa barrier” was born while I was working as a postdoc at Northwestern.
What do you think has been your most influential work to date and why? Scientifically, it is easy to say some work by Dr. Fred McLafferty, but also some studies by Dr. Scott McLuckey and Dr. Jim Stephenson. The reason is the same: they were ahead of their times. McLafferty pioneered the top-down approach, and the work of Stephenson and McLuckey on ion-ion reactions in the gas-phase is at the base of most of the new data acquisition methods I am working on now – just about 25 years later… But, even if it may sound strange, I believe that the works that really influence my way of thinking are mostly art related.
What do you hope becomes the future of your research? I would like to keep developing new technologies for characterizing intact proteins and then apply these tools to medical research. But for that to happen, top-down proteomics will have to become more robust and easier to carry out.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? There were several, but the one that makes me smile was that it was difficult to be taken seriously when I was about to start my PhD in chemistry, because after my master I took a break and spent some time studying philosophy. One chemistry professor with whom I had an interview for a position in his group concluded that a student who likes to “waste time” with philosophy could not do much in a lab. I am not sure he was right.
What is one thing you want to say to other researchers in the early stages of their independent careers? I am not in the position to provide any advice, first I should further prove myself and do something really good, and then anyway I would wait for a person to come ask me: unsolicited advice may sound arrogant or irritating. But if I had to pick a suggestion, this would be to just do what they truly like and what they believe it is important.
What do you see as the future direction of research in your field? I would not be too surprised to see mass spectrometry challenged by other technologies for the high-throughput study of proteins in a few years from now. That would be an interesting scenario. In the meanwhile, mass spectrometers will become more and more complex and possibly more specialized. We already have some instruments specifically designed for single cell “omics” analysis, for example, so I would not be surprised to see systems entirely dedicated to intact protein analysis.
Anything else that you’d like to add? That I was truly honoured to receive the BBA Rising Star Award!
Structural insights into piRNA biogenesis(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
What are the major themes of research in your group? Our group aims to characterize epigenetics-related proteins of biological and biomedical importance by structural analysis in combination with other biochemical and biophysical techniques. Our research would greatly increase the current understanding of molecular mechanisms on how various epigenetic modifications modulate chromatin structure and regulate gene expression, and set up a framework for future research on epigenetics-related diseases and corresponding therapy.
How and why did you come to work in these areas? I became fond of this exciting field during my doctorate study when the profound insights of my supervisor deeply inspired me, and during that period, many new epigenetic modifications were identified and characterized. Those exciting findings are critical in understanding how epigenetic states are maintained and propagated, how they are recognized to affect downstream events, and how effective inhibitors could prevent epigenetic abnormalities at the molecular level.
What do you think has been your most influential work to date and why? The P-element-induced wimpy testis (PIWI)-interacting RNA (piRNA) pathway plays a central role in transposon silencing and genome protection in the animal germline. The N-terminus of the PIWI protein harbors several RG/RA repeats, which can be methylated by the methyltransferase PRMT5. In this work, 1) we determined the complex structure of the extended Tudor domain of SND1 and explained how SND1 preferentially recognizes symmetrical dimethylarginine, which provides a general paradigm for the binding mechanisms of methylarginine-containing peptides by extended Tudor domains. 2) We also found that the extended Tudor domain of TDRD2 preferentially recognizes an unmethylated arginine-rich sequence at the N-terminal of PIWI proteins, and further provides molecular insights into the mechanism of methylation-independent Tudor domain-PIWI interaction. These findings facilitate our understanding of the roles of TDRD proteins in piRNAs biogenesis.
What do you hope becomes the future of your research? 1) Try to understand the molecular mechanisms of more epigenetic events in regulating gene expression combined with different methods, such as structural biology, biochemistry, mass spectrometry as well as mathematical approaches.
2) The abnormalities of epigenetic modifications and epigenetics-related proteins cause various human diseases. Thus, I would like to focus on the development of new therapeutic targets with more specific therapy in the future.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? It is more and more difficult to obtain sufficient funding to support our research projects and research facilities for young scientists. However, I am fortunate to receive some support from the government funding agencies and my university since I became an independent PI.
What is one thing you want to say to other researchers in the early stages of their independent careers? Stay focused and motivated. Follow your passion and have fun.
What do you see as the future direction of research in your field? Many interesting questions remain to be answered in epigenetics, including epigenetic inheritance, epigenetic reprogramming, epigenetic-related diseases and drug therapy.
Enhancing immune checkpoint blockade therapy of genitourinary malignancies by co-targeting PMN-MDSCs(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
What are the major themes of research in your group? My group addresses the challenge on how to overcome the immunosuppressive force in the tumor microenvironment in order to enable or enhance the efficacy of cancer immunotherapy. We explore this question in various cancer types, including prostate, breast, kidney, pancreatic, and a rare cancer type, penile cancer. Both primary tumors and metastases are under our active investigations. Most of our focus has been on tumor-infiltrating neutrophils equipped with immunosuppressive activity, sometimes referred to as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs).
How and why did you come to work in these areas? I started to work on the areas of immunosuppressive myeloid cells and cancer immunotherapy in my postdoctoral research with Dr. Ron DePinho at MD Anderson Cancer Center, around 2015, when the cancer field became increasingly excited about the power of immunotherapy and started to implement strategies to increase the response rate of patients to immune checkpoint blockade therapy. In our transgenic mouse models of metastatic prostate cancer as well as in clinical prostate cancer specimens, we identified an abundant infiltration of PMN-MDSCs (i.e., immunosuppressive neutrophils). My previous PhD research experience in metastasis-associated myeloid cells, mentored by Dr. Yibin Kang, made it smooth for me to focus my research on characterizing PMN-MDSCs and demonstrating the potential of enhancing immunotherapy by targeting these immune cells. After establishing my own group at University of Notre Dame, I continued my quest of the biology and therapeutic targeting of PMN-MDSCs, and expanded the research to a broader topic of utilizing the cancer genotype-immuophenotype relationship to guide new immunotherapeutic opportunities.
What do you think has been your most influential work to date and why? In the last five years of my published research, I would reckon that three studies were most influential: at DePinho lab, my study illuminated the potential of combining MDSC-debilitating drugs and immune checkpoint inhibitors to treat metastatic castration-resistant prostate cancer (Nature, 2017); at my own lab, we uncovered a novel mechanism where MDSCs suppress cytotoxic T cells by nitrating and impairing LCK protein (PNAS, 2018), and we established the first transgenic mouse model of penile cancer with which we showed the central role of MDSCs as a targetable immunosuppressive population (Nature Communications, 2020). I think these works are influential, because they all provide the strong rationale and plausible strategies to target MDSCs (especially immunosuppressive neutrophils) as a potential common denominator to improve immunotherapy.
What do you hope becomes the future of your research? I hope that my research can be translated to clinical benefits in the near future. Although most of my research is at the basic and preclinical stages, I always keep in mind how to connect our models and experiments to the clinical reality and challenges of immuno-oncology. My group actively collaborates with medicinal chemists and clinicians. I hope some of the emerging ideas and reagents from our research can one day bring hopes to cancer patients.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? One major challenge happened in the middle of my postdoc career, when I felt a little lost and wondered about the promise of my research and even the career choice. I overcame the anxiety and uncertainty by deeply thinking why I entered the biomedical field and what I wanted to become. The tremendous guidance from my mentors and the unconditional support from my family all played paramount roles for me to refocus on what was most important and meaningful for me to do and achieve. This experience actually made me firmer and more confident about my career plans and research endeavours.
What is one thing you want to say to other researchers in the early stages of their independent careers? I am not sure if I am qualified yet to give advice to other independent researchers, as I am myself still learning everyday from others and my own mistakes how to become a better researcher and educator. If I could share one thing, it might be: focus on what you are best at and maximize the full potential out of it.
What do you see as the future direction of research in your field? I envision that cancer immunotherapy will continue to evolve and march forward in the next decade to claim successes in our fight against cancer. Strategies to inhibit immunosuppressive myeloid cells with limited toxicity will be moved to clinical practice to enhance various types of immunotherapy. Research on rare cancers and non-traditional interventions (e.g. diets, exercise, holistic therapy) will gain more attention and generate more impact on cancer care.
Anything else that you’d like to add? I would like to express my deep appreciation to BBA Reviews on Cancer and the award selection committee for recognizing the significance of our work. This award will enhance the visibility of our research to the cancer community, open new collaboration opportunities, and promote the potential translational process of our findings.
Antiviral peptide engineering for targeting membrane-enveloped viruses: Recent progress and future directions(opens in new tab/window) Biochimica et Biophysica Acta (BBA) – Biomembranes
What are the major themes of research in your group? Our group is broadly interested in developing lipid-based engineering strategies to address global health issues such as viral pandemics and antibiotic-resistant bacteria. Our research approach is grounded in membrane biophysics and we seek to understand the fundamental biomacromolecular interactions involved in these biological systems. A key theme of our research is to develop biomimetic phospholipid membrane platforms that can be integrated with surface-sensitive measurement techniques to track real-time interaction processes. These measurement capabilities allow us to investigate the membrane-disruptive properties of antimicrobial peptides and lipids in a predictive manner that provides insight into potency and mechanism of action. Such testing platforms also guide us to develop optimized cocktails and nano-formulations for specific applications in healthcare, biotechnology, cosmetics, and agriculture. For example, we are interested in engineering antiviral peptides to inhibit membrane-enveloped virus particles in a curvature-selective manner as well as in translating such capabilities into developing medical devices like an antiviral blood filter. Recently, we have also begun exploring how lipid-based approaches and biophysical measurement strategies can be useful to improve cancer immunotherapy outcomes, which is an area where we have seen very promising results so far and huge growth potential.
How and why did you come to work in these areas? I began my research career by studying the fundamental interactions of phospholipid vesicles with material surfaces such as silica, titania, and gold. These early experiences were mainly done in the context of solid-supported model membrane platform fabrication, which provided critical opportunities to deeply think about the interfacial science behind such interactions and to gain an appreciation for rigorous materials characterization. One day, still during my undergraduate studies, I came across a very exciting paper that talked about how an antiviral peptide could rupture lipid vesicles and, from that day, I was hooked on investigating the biomedical applications of model membrane platforms and have not looked back. I guess it is the centrality of lipid membranes to biological life that fascinates me and it is awe-inspiring how we can use engineering approaches to study lipid membranes and develop healthcare solutions based on the resulting biophysical insights. By working with wonderful mentors and collaborators, I’ve been fortunate to investigate an exciting range of membrane-related biological problems and try to encourage my group members to always look for new problems too. When you realize that lipid membranes are all around us, the possibilities are limitless.
What do you think has been your most influential work to date and why? One of the most exciting projects involved developing a brain-penetrating antiviral peptide to therapeutically treat Zika virus infection in vivo. The project was very interesting because it combined antiviral peptide engineering and membrane biophysics with molecular virology and pharmacology, and involved a diverse team of researchers working together to solve a major healthcare problem. A really fascinating part was our discovery that the peptide could cross the intact blood-brain barrier (BBB) in order to directly inhibit infectious virus particles in the brain and curb neurodegenerative effects of the viral infection. This was all the more exciting because we were actually using a clinical isolate of the Zika virus, which had been obtained in Brazil during the 2015-2016 epidemic there and gave us hope that the study findings could be practically applied. These results led us to define the Lipid Envelope Antiviral Disruption (LEAD) concept as a next-generation antiviral strategy to stop membrane-enveloped viruses, which is now being explored against various viral pathogens. Considering the COVID-19 pandemic and other viral threats, I hope that this antiviral peptide technology will soon reach the clinic and become a key tool to stop future viral outbreaks.
What do you hope becomes the future of your research? I hope that the lipid-based engineering strategies developed in our research will become clinically useful to solve major healthcare problems such as combating future viral pandemics, dealing with antibiotic-resistant bacterial infections, and improving treatment outcomes for cancer immunotherapy patients. To achieve this goal, we will continue our fundamental membrane biophysics research while adopting a more translational focus to develop and optimize pharmaceutical drug candidates that can be useful for addressing such medical needs. For example, in our antiviral peptide research, much of the work so far has been at the proof-of-concept level and sets the stage for peptide engineering to boost performance and to explore a wider range of possible sequence spaces. I am particularly interested in understanding how biophysical measurement platforms can become an effective tool for pharmaceutical drug development. In addition to healthcare applications, I hope that our research group will also become more active in pursuing collaborations with the agriculture and biopharmaceutical manufacturing industries, which are fields where there is potentially quicker translation of lipid-based engineering strategies into practical applications.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? A major challenge I faced in my career was convincing the research community that targeting the lipid membrane surrounding enveloped virus particles could be a viable antiviral strategy. Many researchers wondered whether targeting enveloped viruses alone would be a useful broad-spectrum antiviral strategy because there are also many non-enveloped viruses as well as potential issues of selectivity and potency. This challenge was especially prevalent because our research was grounded in biophysical measurement approaches, which are quite distinct from classical biological approaches used by virologists. To overcome this challenge, we realized that we need to form strong collaborations with other researchers with complementary backgrounds and skill sets in order to build up a truly interdisciplinary research program that could tackle the problem from multiple angles. This experience reinforced in me the value of teamwork and helped us to build strong experimental support to validate the promise of targeting the viral envelope. During the COVID-19 pandemic, we also became interested in comparing the number of membrane-enveloped and non-enveloped viruses that caused recent outbreaks based on a literature review. Intriguingly, we discovered that the vast majority (>85%) of recent epidemics and pandemics were caused by membrane-enveloped viruses, which has lent further support to the merits of our biophysical-driven antiviral research direction.
What is one thing you want to say to other researchers in the early stages of their independent careers? Research breakthroughs come from following your passion and enjoying the scientific process. Inevitably, popular research trends will change over time and it can feel like there is a pressure to follow the trend, especially at early stages in your career when you do not want to miss out on the next big thing. If you want to change topics, it is perfectly fine to do so but if you really like what you are doing, just keep doing it. Over time, you will become the world’s expert on the topic and be in a position to do great research, especially when working in teams which can create tremendous synergy. In some cases, your efforts might lead to the next big breakthrough and, even if they don’t, you will still enjoy what you are doing and that is the most important part of being a scientific researcher.
What do you see as the future direction of research in your field? I think that the membrane biophysics field will take an increasingly translational focus to expand on the quest for fundamental scientific knowledge by also utilizing biophysical measurement approaches in more applied directions. We are already seeing a lot of great activities in this direction worldwide while I think the pace and intensity will continue to ramp up, and there is huge potential to build strong academic-industry collaborations in this space. The current global interest in lipid nanoparticle technology is the latest example and there are many other subjects related to membrane biophysics that are ripe for commercialization. At the same time, a continued focus on fundamental understanding of lipid membrane properties will be paramount because innovation comes from deeply understanding a system and translating this knowledge into practical inventions that solve a problem in society.
Anything else that you’d like to add? It is my great honor to receive the inaugural BBA Biomembranes Rising Star award and I would like to give special thanks to my mentors, colleagues, and group members who have contributed to this research and made everything possible. Membrane biophysics is a very exciting field and I believe that it will be a cornerstone of future biomedical innovation, especially in areas like preparing to stop future virus pandemics and improving response rates to cancer immunotherapy.
Identifying and targeting the molecular signature of smooth muscle cells undergoing early vascular ageing(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
What are the major themes of research in your group? My groups’ research is in the molecular mechanisms leading to vascular disease. Whilst I am interested in all types of vascular disease, my research has so far focused on the vascular complications of type 2 diabetes and abdominal aortic aneurysms. The prevalence of disorders such as diabetes and aneurysms increase with age and, as the world is moving more and more towards promoting a longer health-span as well as life-span, the research from my group could have a real impact on translating into patient benefit. With this in mind, we are now expanding into clinical diagnostics routes, as well as basic science, to advance knowledge in this area and bring us a step closer to helping patients.
I have worked on smooth muscle cells, which are the major structural component of your blood vessels, for the majority of my career and I find them fascinating. All my research is conducted on cells or tissues kindly donated from patients through our links with local hospitals and ethical bodies. My vision for my group is to develop the next generation of vascular biology experts who can go on to forge independent careers in the field; whether that be through continuing basic research, going into industrial or healthcare roles, or IP development with a view towards improving patients’ lives.
How and why did you come to work in these areas? After completing my first degree in Molecular and Cellular Biology at the University of Huddersfield, UK, I took some time to work as a laboratory technician while I decided which area I wanted to specialise in. This was invaluable in giving me practical confidence in my abilities and affirmed that what I wanted was a research-based career. I ultimately decided on cardiovascular disease due to its enormous socioeconomic burden and completed my doctoral studies at the University of Leeds, UK, in Cardiovascular Medicine. My project examined how the hypoxic environment immediately after a heart attack impacts on molecular repair pathways in the human heart and was supervised by Dr Karen Porter and Professor Chris Peers. From this, it was a natural step to look at the blood vessels supplying the heart and thus my career-long obsession with vascular biology was born!
What do you think has been your most influential work to date and why? I am a cell biologist and biochemist at heart, and the work I’ve done throughout my career – both as a Postdoctoral Research Fellow at the University of Leeds with Karen Porter and as an independent researcher at the University of Bradford – has advanced the knowledge and understanding of signalling pathways in the exact cells that are involved in disease: human vascular cells. I am very proud of this body of work and the potential it has to translate into new therapies. As a basic science researcher, the translation to patient impact is a long journey and thus the true influence of my research on healthcare will take many more years to come to fruition.
One of the aspects of my work that has been more immediately influential is the research I also conduct into promoting inclusivity, diversity and embedding mental wellness in postgraduate study. When researchers suffer, then research suffers and so improving research cultures and environments for our up-and-coming scientists is something I am passionate about. I am working with UK advisory bodies and educational developers to influence policy on researcher work practices to help keep our future scientific workforce sustainable.
What do you hope becomes the future of your research? I will continue my foray into translational development to ensure my basic research has true clinical impact. Alongside this, I would like to develop my research in two areas. Firstly, the basic research that we undertake in my laboratory can be applicable for many medical conditions, not just type 2 diabetes and aneurysm disease. I am very open to sharing expertise and collaboration and I would encourage anyone who is interested in what we do to get in touch.
Secondly, I would like to build our expertise in developing new in vitro and ex vivo models of disease which can be used to improve the translational potential of cell-based experiments, and which can help reduce and refine the need for animal research on vascular disorders.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? The biggest challenge I’ve faced in research has come from within. Imposter syndrome has played a major part in my research career, leading to constant self-doubt and missed opportunities through an unwillingness to put myself forward for things. In keeping with my work promoting wellbeing for postgraduate researchers, I engaged in cognitive behavioural therapy to overcome imposter syndrome and though it was a tough journey it was definitely worth it! Building my confidence has had tangible outputs in terms of funding successes, publications, career development and even this BBA Rising Stars Award.
Imposter syndrome is very prevalent in academia and can affect anyone, even those academics who appear – on the surface at least – to be profoundly confident. My message would be to take advantage of the help that is out there, know your worth and through that you can unlock your potential and drive your research to the next level.
What is one thing you want to say to other researchers in the early stages of their independent careers? Recognise and celebrate your achievements! Research is so rewarding but can also be quite brutal with high pressure and high rejection rates for funding and publications. Putting applications and papers together takes a lot of time and effort and I always celebrate submissions as well as subsequent acceptances. When I started as an independent researcher, I shared an office with a colleague at the same career stage and we had an ‘Achievements Board’ which we put on the wall. We filled it in with submissions, successes and anything we were proud of on a monthly basis and it really helped us to recognise the breadth of work that goes into being an academic, and see that success isn’t simply the hard outputs of papers and grants. It helped maintain morale when we were going through those inevitable periods of rejection and was also very helpful for putting together promotion or career development applications.
What do you see as the future direction of research in your field? Humans are exquisitely unique individuals with great variation in the causes and consequences of disease. The ‘one-size-fits-all’ model of therapies is going to have to evolve with our growing understanding of molecular variation and so I feel that the cardiovascular field is going to examine more routes for personalised medicine to better treat the complex individual, rather than simply the disease.
Anything else that you’d like to add? Develop strategies to publish. The big, high impact publications that come from 3-5 years of research are very important but having a publishing strategy that enables 2-3 smaller papers per year alongside this will help advance your career. My PhD supervisor had a rule that ‘no data gets left on the shelf’ and so the smaller side projects, or those projects which did not lead in a productive direction, were still written up, peer reviewed and published in between the high impact papers. I’ve adopted this ethos in my research group and hope that my students continue with it in their future careers. Review articles are also a useful way to become known in your field and can often be borne out of the preparatory reading you do for funding applications. I always have a rolling two-year publishing strategy that helps maintain my productivity and focus, and it’s a good way to get your research group members on the publishing ladder too.
Predicting cancer evolution for patient benefit: Renal cell carcinoma paradigm(opens in new tab/window) Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
What are the major themes of research in your group? Our lab is interested in how cancer evolution underpins the most important clinical phenotypes: malignant transformation, progression, metastases and treatment resistance. Namely, we want to know ihow different genetic trajectories interact with the tumour microenvironment to shape these clinical manifestations of cancer.
How and why did you come to work in these areas? Originally, I became interested in cancer genomics at the time when the first targeted therapies for solid cancer were entering the clinic. Seeing first-hand how effective these treatments were at first only to then fail as resistance emerged, often rapidly, motivated me to study how these dynamics emerged, and if they can be predicted or prevented. Once I involved myself in the field of cancer evolution more broadly I became fascinated by the parallels with other fields, especially evolutionary dynamics in bacterial populations, and of course evolution of species. During this time immune checkpoint blocked had profoundly changed the outcomes of the cancers I was treating in the clinic, melanoma and renal cancer, and I became further interested in the role of the immune system, as both a “predator” and a “facilitator” in the course of cancer evolution.
What do you think has been your most influential work to date and why? I think this is my post-doctoral work in the TRACERx Renal Consortium. Kidney cancer is the most mysterious of solid cancers, and often characterised by contradictions. What preoccupied me in the clinic is the huge variety of clinical behaviour I observed- metastatic disease would sometimes emerge immediately after the removal of the primary tumour, sometimes decades later. Sometimes only a single metastasis in a single organ would present, and other times there would be an explosion of metastases throughout the body, it is bewildering. And yet, the genetics of kidney cancer were very simple- involving a handful of genes, and the mere presence or absence of a particular genetic alterations could not rationalise this clinical diversity. What we uncovered was that the order and combination, as well as the timing of genetic events profoundly influenced how the primary tumour grows and metastasises. It is fair to say that this was the first truly evolutionary classification of a solid cancer; it was hugely exciting. More recently we have built on this knowledge to characterise the genetic and spatial features of the primary tumour cells that are capable of metastases, critically placing the emergence of this competence at the primary tumour site.
What do you hope becomes the future of your research? I am committed to carrying out the type of research that will bring about patient benefit and I am reminded daily, being a clinician, how critical this is. However, I don’t think this path needs to be separated from developing insight into fundamental principles of cancer behaviour, so ultimately I hope my research will contribute both. In concrete terms we aim to contribute these principles through ongoing studies in patients in combination with pre-clinical models, mathematical models and method development so that we can rapidly embed this knowledge in the clinic.
Can you tell us about a major challenge you’ve faced in your research career and how you overcame it? My particular challenge was finding a path as a clinician scientist, which is still not that well travelled in the UK. Ultimately I achieved this by identifying not only mentors but sponsors too, who were invested in my success in the long-term; and through extensive collaboration which is necessary to deliver the breadth of the research programme that I am developing. These are academic as well as industry collaborations which I have thoroughly enjoyed and learned from.
What is one thing you want to say to other researchers in the early stages of their independent careers? It is a point related to the one above which is to seek out people who share in your vision- both peers and seniors. And make sure you are building a career that you will enjoy!
What do you see as the future direction of research in your field? There has been substantial work documenting the patterns of cancer evolution involving genomic profiles, but increasingly, tumour microenvironment composition (spatial biology), immune-phenotyping, TCR sequencing. To move forward our field will need to develop approaches to integrate this information in a meaningful way. This is clearly a challenge given not only the sheer amount of data but its spatial and temporal variation, but it is utterly necessary. Relatedly, we are far from such measurements in routine clinical practice, and we will hopefully be utilising machine learning methods on the type of clinical samples that exist in the record of every patient with cancer no matter where they are in the world (histology, radiology), paving the way for large-scale, real world quantification of cancer evolution.
Anything else that you’d like to add? I would like to acknowledge my lab and clinical teams for their trust and for being such brilliant and inspiring people to work with.