My wife and I used to watch House, M.D. starring Hugh Laurie, in which he was a cranky doctor who happened to be a Holmesian genius in diagnosing rare or mysterious diseases. We are fortunate to have doctors who have much better bedside manner, but as an entertainment option, House was a lot of fun. One of the running gags for fans of the show is that the mystery disease of the week is never lupus, except for the one and only time that it was. My fond memories of this show got me to thinking about how difficult it is to diagnose lupus, and about other autoimmune diseases that still remain mysterious and challenging to treat. I decided to find out how modern medicine is approaching this continuing health issue.

It seems like decades since the SARS-CoV-2 pandemic shut down the world economically and socially, and even now we are not fully out of the woods. The COVID-19 coronavirus continues to persist, hovering on the cusp of becoming an endemic disease after having caused over one million deaths in the United States alone out of over six million deaths worldwide since the first reported cases in 2019. Although the various coronavirus vaccines have conferred some level of herd immunity across the globe, the danger of mutations causing variants that might escape vaccine protection is real, so continued vigilance and best practices are key to returning to normalcy. Perhaps our resolve as a global community and as a species will be tested in short order as the monkeypox outbreaks surge.

Once upon a time when I was a fledgling science nerd in high school, I started learning about the process of apoptosis, which remains to this day the most studied form of cell death in various functions including organismal development and defense against cancer. As an immunologist-in-training, I also learned about the classical complement pathway that the immune system uses to destroy infected cells, and also necrotic cell death or necroptosis (which is full of really gross pictures if you dare to Google it). Of course, I learned about autophagy in graduate school and really appreciate its utility in normal physiology and disease, while very recently I read about ferroptosis as yet another programmed cell death (PCD) pathway. Right around when the Nobel Prize was awarded to recognize the elucidation of PCD, pyroptosis came about as a novel PCD pathway that is continuing to gain steam in its clinical relevance. It seems logical for cells and organisms to have redundant systems in place to clear away damaged and malignant cells before a health crisis can emerge if the cell evades the primary route of apoptosis.

My first experience in a basic research laboratory was a structural biology project, in which we were attempting to solve the structure of a nervous system protein known as myelin basic protein (MBP). As a rookie undergraduate scientist at the University of California, I had great mentors who taught me everything, from how to purify recombinant proteins from bacteria to doing library work to understand what had been done before so I could build upon it. I also learned how to use an electron microscope (EM) to gather structural data. MBP was an interesting challenge as it had multiple isoforms due to alternative splicing, and generally behaved like a random coil. ¹ The major function of MBP is to take advantage of its highly positive charge to compact myelin in higher organisms, with research over the years suggesting it may have some capacity to form alpha helices, although atomic-resolution structures have not yet been reported. MBP has also been reported as a biomarker in autoimmune diseases such as multiple sclerosis. ¹

Before my grandmother passed, she had been battling severe dementia for a very long time, which made it difficult in many ways to have conversations with her. It would take several minutes for her to process who I was, and then it would seem like she would remember me and my family, but she would still have to ask for clarification several times even after we had answered her queries. I am grateful that she is in a better place now, but her challenges in the final years of her life deepened my empathy for people who suffer from dementia, and those who take care of them.

Every now and then when I get hungry, I joke that my stomach is about to digest itself. For the longest time, human science was unaware that our cells could literally eat itself (or more precisely, parts of itself) as well! First described in the 1960s by Christian de Duve (who won the Nobel Prize for discovering the lysosome), the term autophagy derives from Greek words combined to mean “self-eating” and describes a process by which the cell degrades large components and organelles in a distinct mechanism. ^1-3 The phenomenon was not studied extensively until the 1990s, when Yoshinori Ohsumi performed a series of groundbreaking experiments to determine the underlying mechanisms of autophagy, an achievement for which he was awarded the 2016 Nobel Prize in Physiology or Medicine. Ohsumi’s work has led to an explosion of research that has precipitated a greater understanding of the role played by cellular digestion, degradation, and recycling pathways in human health and disease.