ECR Spotlight – Sarah Little-Letsinger Free

Sarah Little-Letsinger

How did you become interested in biology?

While I've been interested in biology for as long as I can remember, I don't really know where it came from. The natural world, and particularly the human body, always captivated me. Growing up immersed in sports, I first sought a career related to Sports Medicine. After toying with the idea of physical therapy, I decided to pursue Exercise Physiology as a graduate student. It was there that I became enthralled with how microscopic mechanics could explain macroscopic phenomena. My institution's graduate training program in space medicine drew me to the musculoskeletal system, and bone in particular. My doctoral research in bone biology then led me to postdoctoral exploration of the intricate and fascinating bone marrow microenvironment – a complex, multi-system hub that deepened my appreciation for biological complexity. This appreciation has continued to grow, as in my second postdoc, I've acquired an evolutionary lens to the study of osteoimmunology that has broadened my perspective from osteoporosis to the fascinating realm of vertebrate evolution and evolutionary physiology. Given my prior trajectory, my love of biology can only keep growing!

Describe your scientific journey and your current research focus

My scientific journey began during my masters in a molecular muscle lab. I loved histology, but I struggled with how molecular the work was and muscle wasn't my passion. A brief foray into sports performance and data analytics also proved to be the wrong fit. But then I came across bone biology, through a lab in my graduate program. I recall trying to explain to my soon-to-be doctoral advisor, Sue Bloomfield, why I wanted to study bone. I didn't have a good answer, and I still don't. There's just something about bone that is intoxicating to my brain. At the time I was studying how inflammatory signaling in osteocytes caused bone loss, contrasting space-relevant radiation with diet-induced obesity. And I loved it! During this work, I kept noticing bone marrow adipocytes in my slides (see research photo), and how widely they were varying across my groups. I pursued my first postdoc in a joint lab studying bone marrow adiposity and mesenchymal stem cells. It was around this time that I encountered two pivotal areas that changed my scientific trajectory for good. First, I became fascinated with the immune side of bone marrow. I began to understand my work on inflammatory bone loss in ways I could never have imagined coming from a classical bone mechanobiology lab. Second, I discovered the concept of skeletal gracilization, or that modern humans have lower bone mass and strength compared to our human ancestors. This was my first exposure to bone research outside of a biomedical setting. I couldn't stop thinking about the intersection of osteoimmunology and evolutionary anthropology, and it wasn't long before I discovered the work of a collaborator who would give me a theoretical mechanism for the ideas swirling around my head. Around this time, I began a second postdoc in Evolutionary Anthropology. Since then, I've been fortunate to be able to explore so many aspects of skeletal evolution, including functional demands imposed by locomotion, theoretical modeling of bone robusticity, and to pursue my own mechanistic work developing a novel theory of how bone has evolved to predispose humans to spontaneous fracture.

How would you explain the main findings/message of your paper to a member of the public?

Walking on two legs is a pretty unusual thing in the animal kingdom. While humans aren't the only two-legged walkers, most scientists agree that walking on two legs was a pretty substantial turn of events for humans. But how humans went from four-legged to two-legged walking is still a mystery. Using data from methods like how bones are shaped to the way living primates and humans walk and run, some have argued that early human ancestors would have walked with deeply bent hips and knees (called a compliant gait), in contrast to our relatively stiff modern gait where hips and knees barely bend at all. Theoretical and some experimental data indicate that compliant walking can lower the peak forces resulting from contact with our body on the ground and that it would do so by changing contact time – meaning that impact of peak forces would be lowered by spreading the forces out over more time. Prior research had never tested this mechanistic link using two-legged walking in living humans, and so our study sought to fill that gap in research. We found mixed evidence that a compliant gait lowered peak vertical forces through contact time. Notably, we found very large increases in lateral (outward) and aft (propulsive) forces with a compliant gait, alongside large reductions in medial (inward) and fore (breaking) forces. We also applied a novel analysis technique to analyze the entire shape of our force traces, rather than relying on one to three distinct peaks, which further illuminated our understanding of forces during walking by identifying precise regions of the gait cycle where differences in forces are occurring between gait styles. The direction in which the forces are varying can tell us deeper information about where to look in the body. For instance, a compliant gait is usually defined by motion at the hip and knee, but what is most exciting about our new data is that it points to a critical role for the foot and ankle in the evolution of bipedalism – an area in need of further exploration!

Why did you choose JEB to publish your paper?

Is there a scientist who has heard about JEB that doesn't want to publish in JEB? Maybe the coolest journal I know of! In all seriousness, when I'm looking for a paper that is novel, creative, and is of high rigor, JEB is the place to go. Of course, JEB is also a great fit for this particular research paper on the evolution of bipedalism. Much of the prior work we relied on in our investigation has been published by JEB!

What do you enjoy most about research, and why?

I love so many things about research, it's hard to pick one. The joy of uncovering new knowledge can't be understated. I love thinking about things in new ways, considering what we know versus what we think we know versus what we might have gotten wrong. In terms of value and meaning creation, I don't know of another activity that enriches me more in those areas. I also love learning from failure – it's the only way I can be really sure that I learned something. If I got something right, it's hard to say if why I think it succeeded is true or if it worked but for a different reason. The opportunity to have clear feedback and to be able to apply that to move forward or try again is just so valuable. Besides, there's something really special that happens when you can iterate something over and over again. It's like a secret cheat code to unlock some special insight. And the feeling of mastery! Now that doesn't come for many years and it often comes and goes, but it's a pretty fantastic feeling. Lastly, research is a really special job. The public trusts you and funds you to solve some of the hardest problems we're facing as humans, to illuminate areas of darkness, and to help build our future, and there's a real magic in getting to do that for a living.

What is the hardest challenge you have faced in the course of your research and how did you overcome it?

Creating something with nothing! My postdoc funding comes from teaching, which means that I was afforded a lot of research freedom but that I was not provided research funding. I had to find ways to produce new research with little to no funds. It's hard to give specific advice about how I overcame my lack of funds, aside from relying on publicly available datasets and writing grant after grant after grant. I had to learn to scale down my ideas to find the foundational, essential thread and then figure out to answer that question with as few resources as possible – a process that took many, many failed attempts. There are certainly intangible aspects that drove me forward, like a stubborn belief in myself even when I had no real evidence to back it and a strong support system. My husband is a postdoc too and, while we are in different fields, having a science buddy is of immense value. Being able to talk things through and brainstorm with another person, whether that is your friend, partner, coworker, or mentor, is invaluable. I think, ultimately, the secret to any hard challenge is to persist, and I think that takes a deep enjoyment of the journey. So, I guess my best advice would be to find something you love to persist at, even when it feels impossible and even when you fail over and over again.