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1. The Compatibility Gene made me appreciate the vast amount of research that contributed to the understanding of the types of immune cells exist and how those cells work to combat the wide variety of pathogens that we encounter throughout life. One of the most resonating pieces of this book was the stories of Peter Medawar and how he conducted his research. Throughout the novel, Medawar is painted as a workaholic driven to find an answer to transplantation at any cost. He spent long hours conducting extremely large animal transplant studies that ultimately led to his Nobel Prize award. There was even a small aside in the book about how his wife would ask before speaking to him so that she would not interrupt his thinking. I think this demonstrates the ambition and dedication that these scientists had (and even those around them had to have) to find answers to questions that we now take for granted in our understanding of the immune system as a whole.

   Beyond chronicling the discoveries that led to our modern understanding of the compatibility genes, the novel discusses the importance of genes in plainest terms. It describes the well-known examples of genetic diseases such as cystic fibrosis and sickle cell to introduce how compatibility genes fit into human health in general. The author describes how the variations of our compatibility genes influence our susceptibility to other diseases or infections such as HIV and how certain compatibility genes can protect from infection or even predict the efficacy of the drug treatments. I thought this was an interesting bit of information to include in a popular science book that helps to demonstrate the power of certain molecules within our body and their wide ranging effects on infection, disease progression, and treatment efficacy.

   The final chapter opens by discussing how the compatibility genes help with the recognition of non-self (such as a fetus during pregnancy) and how that recognition leads to an immune response. Medawar was one of many who was interested in how the body can tolerate a fetus but rejects a transplant when both situations have non-self present. Of particular interest was how the trophoblast cells, those that are most intimately connect a mother and a fetus, interact during pregnancy without rejection. One answer to this was that immune cells do not reach the uterus during pregnancy but, many independent researchers including Billingham who had previously worked with Medawar, found that immune cells do reach the uterus. This left many researchers wondering what types of immune cells are present and how are they not activated during pregnancy? Ashley Moffett played an instrumental role in the discovery of uterine natural killer (uNK) cells as described in this chapter. She began as a pathologist in a maternity hospital and her desire to identify the immune cells in the uterus ultimately guided her into a career in research. Along with two other female researchers, Judith Bulmer and Phyllis Starkey, the immune cells in the uterus were identified as natural killer cells. Since the discovery, a lot of additional research has been conducted regarding the function and the role uNK cells during pregnancy. Moffett has also found that certain types of compatibility genes along with NK cell receptors did increase certain pregnancy complications such as miscarriages, pre-eclampsia, and poor growth of the fetus. With these correlations, she concluded that uNK cells were likely a protective mechanism within the uterus to help facilitate healthy pregnancy. Moffett has continued to research the role of uNK cells and their impact on pregnancy. She authored a review in the Journal of Clinical Investigation in 2014 regarding the active regulatory role that uNK cells have during pregnancy. In the review she describes the role the uNK cells play in placentation and aiding in the formation of the vasculature of the placenta as well as highlighting some key differences between peripheral blood NK cells and uNK cells. The review ends optimistically discussing the possibility of uNK therapeutics to alleviate pregnancy complications.

   Overall, I thought this book was interesting for both immunologists and anyone who enjoys popular science books because it tells the story of the compatibility genes in an accessible and exciting way. It provides some of the life details of the scientists who were instrumental in these discoveries that helps those who know about these discoveries humanize those that they have read about in textbooks. At the same time, it provides enough information for someone who is unfamiliar with the field to understand the contexts that these discoveries were made in, what the implications for these discoveries are now, and what research is currently underway to follow up the discoveries.

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2. The Compatibility Gene by Daniel Davis: Some thoughts

   As a T cell biology lab, we figured this would be a largely easy read that presents some intriguing research on non-immunology implications of MHC in physiology and even population biology. However, I found the first section that provides a history of the discovery of MHC’s role initially in transplant (for which the molecules are named) and eventually in basic immunology to be the most interesting. Davis does a great job of highlighting the particularly circuitous and serendipitous path needed to be tread to understand this curious molecule. As a budding scientist, I enjoyed the affirmation his account provided me, that all the setbacks and frustrations we face when doing science are common and expected, and that even the gods of immunology were not immune from them. I found learning that it took Pam Bjorkman 8 years to solve the structure of MHC-I but also understanding how impactful her hard-earned discovery was to be encouraging and inspiring. The insights into the researchers’ career paths, personalities, and quirks were quite humanizing, though I fear Davis went a bit too far in a few instances: citing Niels Jerne’s sexual proclivities was wholly unnecessary as was the discussion of the strange circumstances surrounding Don Wiley’s death (and were likely added to spice up the story for non-scientist readers). All things considered, I found the first section to be surprisingly enjoyable and enlightening.

   When considering this book through the eyes of a non-scientist reader, I feel the first section did an effective job of introducing a particularly challenging aspect of biology in a digestible way. Further, I feel that the layperson also benefits from the circuitous story telling as it hopefully imparts that science typically does not progress in a linear, purpose-driven fashion that non-scientists often believe it to. I think Davis was smart to use Dr. Bjorkman’s MHC-I crystal structure to synthesize the work leading up to that point. However, I believe he missed an opportunity to communicate that we still do not know what the role self-recognition, that the T cell recognizes both the antigenic peptide and MHC, plays in immunology. Davis appropriately explains Zinkernagel and Doherty’s experiments establishing the necessity of self-MHC recognition, but why must T cells recognize MHC at all? We can imagine an MHC* that holds peptides like a lollipop, the peptide being the candy on the end and the MHC* as the stick, as opposed to cupping the peptide like a hotdog in a hotdog bun as Dr. Bjorkman discovered. With such a structure, the TCR could bind the presented peptide without interacting with the MHC* at all. I would argue that T cell antigen recognition and even positive selection on self-antigens in the thymus could work to the same effect using an MHC* system but would eliminate the issue of major histo-incompatibility (though of course organ transplant would not have played a role in the structural evolution of MHC as it does not provide a selective pressure). So, why take on the risk of recognizing self-molecules? The short answer: we don’t know. This could have been an interesting frontier of basic immunology that Davis could have highlighted.

   The remaining chapters were used to discuss selected topics related to MHC and were variably informative. Chapter 5 effectively discussed the impact of HLA polymorphisms on human disease, highlighting the clinical importance of MHC research beyond transplant, while chapter 7 covers the discovery NK cells and demonstrates the complex whack-a-mole game our immune system plays with pathogens. Conversely, I found chapter 6, which covers “big data” and bioinformatics, to be completely out of place in this book as well as being not terribly informative to the layperson. To round out the book, section 3 features three avenues of study that explore how MHC diversity can impact non-immune aspects of human biology. Of these three, chapter 8 which introduces the potential role MHC plays in mate selection, possibly through smell, was the most interesting and detailed. Davis opens by discussing a study by Claus Wedekind that interestingly showed that women found the smell of men with dissimilar HLA types to be more attractive than those that were more similar. This is certainly an intriguing idea as it would imply that we are hardwired to find mates with complementary immune systems, thus maximizing immunological diversity at a population level. Davis appropriately discusses the severe skepticism these results have received since they were published in 1994. In addition to the small effect size in Wedekind’s own study, there has been significant methodological questions as well as conflicting reports in subsequent studies that limit the impact of any findings in this field. For example, how is “attractiveness” or “sexiness” defined, and, further, how does it vary between cultures? My bet is that MHC compatibility could play a role in mate selection but it likely plays a vanishingly small one for humans compared to social and cultural factors.

   I found the Compatibility Gene to be an enjoyable and interesting read! I would recommend this book to scientists and non-scientists who are interested in learning about fundamental concepts in immunology, though I admit, it may take more dedication to the topic to get through the first section than other popular science books.

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