Although the phenomenon of cell death had been known for centuries, even briefly described in the 19th century, the explosion of research and technology in the latter half of the 20th century led to greater and more nuanced discoveries that have provided insights into many physiological processes including tissue development, maintenance, metabolism, and disease states including cancer. The many accomplishments in programmed cell death research have improved our understanding and development of targeted therapeutics, and some of these milestones were recognized by Nobel Prizes for apoptosis and autophagy. As scientists continue to elucidate new cell death pathways and their interplay with other pathways, let's take a look at what we know so far and what new findings have come out.

The term apoptosis was first used in 1972 to describe a morphologically distinct form of cell death. Since those early experiments and observations, apoptosis has become one of the focal points for biological research, with myriad laboratories and research groups continuing to work to further elucidate the components and pathways that drive this programmed cell death. As a fundamental biological pathway, apoptosis has benefits and adverse effects for the host organism. For example, many therapeutic strategies involve the activation of apoptosis to kill cancer cells, while other treatments seek to prevent apoptosis to preserve precious cells in key tissues. 

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.

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.

When I was growing up in Hong Kong, and even after I came to the United States, my parents and grandparents would periodically give me ginseng beverages and soups, which was not always pleasant due to the bitter taste. As a result, I don’t think I really appreciated the benefits of ginseng, both scientifically confirmed and perceived. It is fun and informative to read about the myriad studies of natural plant extracts and how they can improve our well-being. Many folks like to drink herbal teas or use plant-derived supplements such as aloe vera lotions, so maybe this is good incentive to grow more of these beneficial plants such that they can provide health products as well as some clean oxygen for us to breathe!

A Bird’s Eye View of Necroptosis

Necroptosis is a type of regulated necrotic death driven by defined molecular pathways. Regulated necrosis regulates programmed cell death. Necroptosis is at the center of the pathophysiology of several clinically-relevant disease states, including myocardial infarction and stroke, atherosclerosis, ischemia-reperfusion injury, pancreatitis, and inflammatory bowel disease. Necroptosis results in necrosis-like morphological changes, such as cell swelling, plasma membrane pore formation, and membrane rupture. It also requires co-activation of receptor-interacting protein (RIP) 1 and RIP3 kinases. Necrosome is a complex formed by RIP1, RIP3 and Fas-associated proteins with death domain (FADD). Several studies in the preclinical stage have demonstrated that targeting necrosome can have variable effects on progression of tumors, indicating that it is largely cell-type or context dependent.