David Kennedy and Andrew Read have kindly supplied the following teaser for their latest paper in Proceedings Of The Royal Society B. As they point out, this “armchair speculation” has elicited a gamut of reactions ranging from awe to scorn and so we are sure they would welcome commentary on this paper from the readers of Evmedreview!
Dave Kennedy and Andrew Read
Center for Infectious Disease Dynamics, Departments of Biology and Entomolology, Penn State
Evolution is perhaps the world’s greatest problem solver. It has found innumerable solutions to blistering environmental insults. Nowhere is this clearer than for drug resistance. Pathogen evolution has undermined virtually every known chemotherapeutic drug. Yet rubbing a cowpox pustule into a person’s open wound somehow confounded evolution. Most modern vaccines have done so too: they work as well as they did when they were first introduced. Why can evolution rescue pathogens from drugs but not from vaccines?
When we first discussed this question, we were surprised not to agree on an answer. It seemed that any of a laundry list of features might help explain why vaccines are more evolution-proof than drugs. We were also surprised to find barely any discussion of the problem in the literature. A few people had asked why resistance to measles or smallpox vaccines failed to evolve, but the answers were specific to those viruses. What was the general answer?
We disagreed for months before one of us (DK) persuaded the other (AR) that, ironically, the most plausible answer lay in processes well known in agricultural resistance management. This solution—which we just published after a grueling time with reviewers—is essentially armchair speculation. We cannot yet know whether it is correct. Reactions from colleagues have ranged from ‘that is obvious’ to ‘that is wrong’ and have involved adjectives like ‘superficial’ and ‘stimulating’, as well as the opinion that our article reads like an undergraduate essay. We hope that the simplicity of our argument breeds the kind of skepticism that leads to new data and new theories. The problem seems important. Will next-generation vaccines fail? Can drugs be made as evolution-proof as vaccines? Which cancer therapies have the greatest potential to work?
What factors should we blame most for the continuing pandemic of heart and artery disease throughout the Western world? The argument has endured more twists and turns than California Route 1. For years, the diet cholesterol hypothesis has held sway, with added blame attached to smoking and a couch potato lifestyle. Before the ascendency of the cholesterol hypothesis, cardiology favored inflammation as the main driving force for atherosclerosis, and interest in inflammation has returned thanks to studies suggesting C-reactive protein is a much better indicator of heart problems lying in wait for asymptomatic individuals than cholesterol levels or high blood pressure; a meta-analysis showing that dietary change has no impact on the risk of a heart attack; studies showing that atherogenic processes in arterial walls are driven by the immune system; and paleocardiology studies showing that pre-industrial and prehistoric societies had high levels of arterial plaque despite high exercise levels and a frugal diet low in saturated fat. i.e. that susceptibility to heart disease is not a modern phenomenon. Now, a study published last Friday in The Lancet, based on measurements taken from members of the Tsimane – a forager-horticulturalist population living in the Bolivian Amazon basin – dramatically switches the argument back again. The Tsimane have extraordinarily low rates of coronary artery disease, low blood pressure, low blood glucose, and low “bad” cholesterol (LDL), despite enduring chronic high levels of systemic inflammation due to the high pathogenic load they carry. It is infection that carries them off – not heart disease.
Further to our feature, a few weeks ago, on the state of health of the amyloid hypothesis – the dominant hypothesis to explain Alzheimer’s disease – comes news of yet another abandoned trial. This time the company is Merck and the drug under test is verubecestat, which inhibits the BACE pathway which produces the beta-amyloid protein. The trial, which has been running since 2012, was stopped because there were absolutely no signs of drug efficacy. Particularly worrying is the fact that this trial enrolled patients with mild to moderate symptoms of Alzheimer’s as opposed to previous trials which tended to target individuals with more advanced forms of the disease. Big pharma is testing the amyloid hypothesis to destruction by sticking to its core tenet that either inhibiting the production of beta-amyloid or hastening its removal from the brain is the correct route to curing Alzheimer’s and enrolling groups of individuals earlier and earlier into the disease process. In the meantime here are a couple of reflective articles published in the wake of the failed Merck trial. The first is a commentary by Derek Lowe in Science Translational Medicine and the second is an article in The Atlantic by Sarah Zhang.
There is an excellent review for the second edition of “Principles of Evolutionary Medicine”, (written by Peter Gluckman, Alan Beedle, Tatjana Buklijas, Felicia Low, and Mark Hanson), in the latest Quarterly Review of Biology. It is written by Robert Perlman of the University of Chicago. Normally, QRB lies behind a paywall, but, as luck would have it, this link to the preview page contains the whole review in a readable format, since it is all on one page.
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