A constructively critical appraisal of the hygiene hypothesis in evolutionary perspective

Book Review: The Hygiene Hypothesis and Darwinian Medicine
Graham A.W. Rook, Editor,Progres  s in Inflammation Research, Michael J. Parnham, Series Editor
Birkhäuser Verlag AG, Basel, Boston, Bern       ISBN 978-3-7643-8902-4

The hygiene hypothesis (David Strachan, Brit Med J 299:1259-1260, 1989) has done much to literally bring immunology into household conversations, in a meaningful and practical way. How should we balance the risk of acutely dangerous infections in our babies and toddlers with a supposedly healthy exposure to environmental microbes and non-infectious agents to limit the lifetime risk of asthma and autoimmune disease? As a light-toned example, in some Western countries, the slightly neurotic midnight sterilization of baby feeding bottles and boiled water has only very recently given way to the much more relaxed use of hot tap water.  However, from a scientific perspective the original hygiene hypothesis posed serious problems from the onset, as borne out by sharply contrasting studies and emphasized by overly optimistic interpretation at points. Obviously, the obstacles for human epidemiological studies to correlate early age exposure to disease later in life are huge and difficult to overcome. Conversely, experimental data using inbred mouse strains in ultra-clean animal facilities can easily be questioned in terms of relevance for the human situation. Nevertheless, the hygiene hypothesis has been a fruitful paradigm to drive and direct research, and it has productively  “morphed” by the accruing evidence.

Dr. Graham Rook from University College London has taken on the laudable task to explore this reworking of the hygiene hypothesis as it stands mid-2009, and to do so from an evolutionary medicine perspective. He recruited 24 experts from different fields to write 15 concise and insightful chapters in 300 pages.

To leave no doubt, this  book is well worth reading.

It provides a highly welcome overview of the hypothesis from different angles, with an understandable immunology emphasis. These include anthropological expertise on epidemiology (George Armelagos), the evidence for relations between infection and childhood leukemia (Mel Greaves), and for the less often discussed implications of the hypothesis for atherosclerosis (Hafid Ait-Oufella and colleagues), psychiatric disorders (Graham Rook and Christopher Lowry), and for Alzheimer disease (Sue Griffin and Robert Mrak). Some authors are actively developing novel therapies to treat bowel inflammation with parasites and their products (David Elliott and Joel Weinstock).

Importantly, the book also addresses limitations to the hygiene hypothesis, as well as alternative and additional mechanisms (Margo Honeyman and Leonard Harrison). Refreshingly, some authors sound clearcut critical notes: for instance, much better definition of the underlying mechanisms are needed for allergy-protective interventions by infection: “Until then, any further attempts to prevent allergies with products lacking a solid rationale have to be regarded as doubtful, empiric and perhaps non-ethical enterprises” (Paolo Matricardi and Eckard Hamelmann).

Throughout the book, Rook’s own notion of Old Friends is discussed, the gut microbiota and environmental saprophytes with whom humans developed dependence through evolution. This is done in a balanced way and the Editor himself states clearly “It is not the purpose of this book to suggest that all of the increase in chronic inflammatory disorders is due to diminished contact with the old friends”.

Does the book leave anything to wish for? Of course it does, but much of that has to do with the truly staggering increase in pace with which the immunology field is developing, and the time it takes to bring a book to print and to the readers desk. For instance, other than the Toll-like receptors (TLR) recognizing both microbial and self molecules, and the NOD receptors responding to bacterial peptidoglycan fragments, the book does not devote much attention to other members the NLR family of innate antigen receptors. The same holds true for the RIG-I like helicases (RLH family), responding to both viral RNA and self DNA when accessing the cytoplasm. The novelty of the recent studies is underscored by a special issue of Science January 15th 2010 focusing on these families in innate immunity. As another example, exciting experimental work on relations between gut flora and obesity was too recent to include in the book.

An item that could have been addressed more in depth, and early on in the book, is the true and primary evidence on worldwide trends in asthma, other allergic afflictions, and the wide spectrum of autoimmune diseases. The book has a scattered 6 graphs on these trends, but only the rise in inflammatory bowel diseases (IBD: Crohn’s and ulcerative colitis) is discussed in depth. Why are these numbers so important? The emphasis in the hygiene hypothesis has always been on allergy, asthma, and on only a selection of inflammatory/autoimmune diseases, mostly type 1 diabetes, IBD and multiple sclerosis. I would argue that much can be learned from a systematic listing of prevalence trends in the spectrum of autoimmune diseases ranging from highly systemic to mostly organ-restricted. Also the female-male ratios within this spectrum, and changes in this ratio – supposedly increasing in multiple sclerosis – is potentially informative. And echoing Mel Greaves’ discussion of population mixing as a factor in acute lymphoblastic leukemia, to what extent have these prevalence numbers been analysed in terms of migration and subsequent alterations in national populations?

Finally, how strong is the evolutionary medicine component of the book? It is well-covered looking back over evolution anthropologically and immunologically. Conversely, how Darwinian theory will stimulate progress in hygiene hypothesis research could have been more strongly developed.

Notwithstanding these remarks, in conclusion, this book is a highly worthwile addition to existing literature. In view of its broadness and depth, and its critical appraisal of the hygiene hypothesis. It is useful for teaching purposes as well as for researchers from different fields, and the chances are good that it will  gain soundbite notoriety as The Rook Book.

Prof.Dr. Jon D. Laman

Department of Immunology, Ee 800

Erasmus MC, University Medical Center Rotterdam