The Angel and the Assassin

Donna Jackson Nakazawa

Summary

The Angel and the Assassin by Donna Jackson Nakazawa discusses the newish science of the role of microglia in both the brain's maintenance and developing, but also in chronic brain inflammation and neuropathology. She is a bit hyperbolic in her assertion that "this tiny cell, the power of which science overlooked for so long, plays some role in every story of human suffering," but the book tries to take us through many different topics, building up to a universal microglia theory of disease.

She begins by discussing the context that all of the research on microglia began. The scientific dogma a few decades ago was that the brain was completely "immune privileged" meaning that it did not interact with the peripheral immune system. Further, the tiny cells that end up being the focus of the book, called microglia, were mostly thought to be lowly janitors and mainly thought of as a nuisance that got in the way of the real neuroscience experiments.

This view began to change around 2012, when Beth Stevens observed that microglia were engulfing and pruning underused synapses. This immediately led to a hypothesis about the role of microglia in pathology, since there was a clear mechanism by which microglia could wreak havoc in the brain (eating the wrong synapses) - since so many brain diseases are associated with a loss of synapses.

This hypothesis seems to be supported. Microglia become activated by various kinds of brain insults and can lead to vicious cycles of inflammation. Dysfunctional, damaging inflammation has been implicated in a number of diseases, including Alzheimer's disease, autism, Huntington's, traumatic brain injuries, obsessive-compulsive disorder, depression and anxiety, Parksinson's, multiple sclerosis, schizophrenia, etc…so Donna Jackson Nakazawa joins some theorists in believing that the dysfunctional microglia are the causal agents in all of these diseases.

She then discusses the link between other immune-related disorders, such as Crohn's disease, lupus, and MS and other auto-immune conditions and mental disorders including anxiety and depression, and considers that they are causally linked. This causal linkage is more plausible because lymphatic vessels were recently discovered in the meninges of the brain, and could conceivably act as a bridge for immune signals to pass between the brain and the rest of the body. Then haywire inflammation from auto-immune disorders in the body could directly cause inflammation in the brain.

She also discusses reasons that auto-immune conditions (both in the brain and in the rest of the body) may be on the rise. She approaches this from two directions. One of them is biological - there are less of our normal evolutionary adversaries in the environment and more strange chemicals that we may be reactive to. This is related to the hygiene hypothesis - that our overly sterile environment does not give our immune system the appropriate feedback it needs to distinguish friend from foe. She also discusses how social signals and other stressors may interact with our brains in negative ways to create inflammation - basically proposing that microglial activation mediates the link between changes in our social environment and increased mental illness across all ages, but especially in children and adolescents.

She spends the rest of the book then following some patients and discussing treatment strategies that try to calm the overactive microglia. She follows three women as they try different approaches, while also discussing the mechanisms of the therapies with their physicians. Katie goes through transcranial magnetic stimulation to alleviate her depression and panic disorder. We also learn about additional neurofeedback approaches with Heather, using real time EEG feedback, who is treating her depression (and later attention) issues. We also learn about immunotherapy interventions, vagal nerve stimulation (or exercises), electroconvulsive therapy, and hallucinogens (mainly ketamine). And we also follow Lila, who has Crohn's disease and is trying a fasting-mimicking diet." In all of these cases, the author describes their treatment as mainly working by affecting microglia activity in the brain.

Outside of the case studies, she also discusses treatment approaches for both chronic pain, and Alzheimer's disease based on reducing immune activity. For chronic pain, she cites research showing that markers of microglial activation in the brain measured in PET scans could predict who would be suffering from pain. For Alzheimer's, she focuses on a therapy that entrains visual areas and the hippocampus in mice at 40Hz by using light, which led to a dramatic increase in microglial clearance of beta-amyloid, which is headed for clinical trials in humans.

The end of the book considers some philosophical points about medicine. She discusses the importance of identifying better diagnostic techniques in order to lead to better treatments. For example, we need to identify Alzheimer's pathology earlier and we need to understand the biology better underlying different kinds of depression. She also discusses how philosophical and scientific history may still be biasing scientific progress - for instance, she believes that the mind-body dualism that we inherited from Descartes makes it unintuitive to think of mental health as connected to the body, and she thinks that Freud's appeal to distance psychotherapy from biology may still have ramifications in how clinical psychologists or psychiatrists think about treating mental illness.

Discussion Questions

I felt like there were lots of scientific faux pas and overstatements in this book. Did anyone else feel that way, and what did you identify?

I really appreciated the "call to arms" to build better diagnostics - partially because it was presented in a way that I haven't seen that much in popular science. In some parts, she was suggesting that we may already have really good treatments, but that our diagnostics are limited. For instance, if we can learn to identify Alzheimer's earlier, our treatments may work much better…or if we can call depression different things based on its etiology, we can treat it in different ways. You need good labels to study things appropriately. What do you think is the best way to refine diagnostic labels while still trying to develop treatments?

Do you really think that mind-body dualism affects our sense of treatment like she suggests? This was surprising to me, because it seems odd that people generally still think of the mind as distanced from the body. It was especially surprising since she was asserting it about how physicians/psychiatrists think of the mind.

I don't mind when science journalists focus on individual's stories to convey a point, but in this case, I felt like Donna Jackson Nakazawa was adding a lot of bias. She was encouraging people to do specific types of treatments that she already believed in. Also, I felt like some of her "scientific evidence" were just things that the treating physician said instead of citing a paper. What do you feel like the best balance is in science journalism?

I thought it was so weird that Donna Jackson Nakazawa proposes a Microglial Universal Theory of Disease (all capitals). I've never heard of this before, and I'm pretty sure that this is an invention of Nakazawa's, not a scientific theory in pathology, which you might think based on how many capital letters there are. It just seemed weird to me that rather than deciding that some kind of microglia activation or dysfunction is correlated with many diseases, she jumps to believing that it causes every disease. Did this seem overreaching to you? Or were you convinced?