Why NIH needs evolution expertise–The amyloid beta case study

Why NIH needs evolution expertise–The amyloid beta case study

Sharon Begley has written a lovely article on Tanzi and Moir’s research on the antimicrobial properties of amyloid beta and the outrageous difficulty they have had getting NIH to fund their work. They noted that study after study has found no benefit from treatments that disrupt amyloid synthesis, and that there must be some reason why amyloid beta exists.

The crucial paragraphs are in italics below

“For years in the 1990s, Moir, too, researched beta-amyloid, especially its penchant for gunking up into plaques and “a whole bunch of things all viewed as abnormal and causing disease,” he said. “The traditional view is that amyloid-beta is a freak, that it has a propensity to form fibrils that are toxic to the brain — that it’s irredeemably bad. In the 1980s, that was a reasonable assumption.”

But something had long bothered him about the “evil amyloid” dogma. The peptide is made by all vertebrates, including frogs and lizards and snakes and fish. In most species, it’s identical to humans’, suggesting that beta-amyloid evolved at least 400 million years ago. “Anything so extensively conserved over that immense span of time must play an important physiological role,” Moir said.  What, he wondered, could that be?

Their subsequent work has demonstrated beyond doubt that amyloid beta is a powerful antimicrobial [1] and has strongly suggested a role for herpes viruses[2]. But despite these findings, they still are having difficulty getting their work published and getting NIH funding. I predict this will lead to a Nobel prize, and go into the history books as an especially egregious example of how pure reductionism obstructs progress.  Evolutionary thinking about the reasons why we are vulnerable to Alzheimer’s disease adds the missing perspective. We can hope that it will also inspire new approaches to prevention and treatment.

  1.  Kumar, D. K. V., Choi, S. H., Washicosky, K. J., Eimer, W. A., Tucker, S., Ghofrani, J., … others. (2016). Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science Translational Medicine, 8(340), 340ra72–340ra72
  2. Eimer, W. A., Vijaya Kumar, D. K., Navalpur Shanmugam, N. K., Rodriguez, A. S., Mitchell, T., Washicosky, K. J., … Moir, R. D. (2018). Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron, 99(1), 56-63.e3. https://doi.org/10.1016/j.neuron.2018.06.030

Photo credit: Creator:Jon ChaseInformation extracted from IPTC Photo Metadata

How EvMed Misled Me—The ASA saga

How EvMed Misled Me—The ASA saga

The history of medicine is replete with examples of the disasters that result when clinical practice is guided by theory alone. For instance, in the early 20th century sudden infant death was attributed to suffocation caused by an enlarged thymus.1 Thousands of infants received radiation treatment that created an epidemic of thyroid cancer, with new cases still emerging 45 years after exposure.2 

Such examples make most of us in evolutionary medicine extremely wary of basing clinical advice on theory. However, recommending aspirin to prevent strokes and heart attacks seemed like a sure thing. In modern environments, bleeding is less of a risk, and clots in coronary or cerebral arteries are a much more of a risk, than in ancestral environments. Taking a baby aspirin every day should adjust the tradeoffs to help our ancient bodies cope better with modern environments.  Also, studies showing that a baby aspirin a day reduced heart attacks by more than 25% led medical organizations to endorse aspirin for prevention.3

The data supported the evolutionary theory, so I started taking a daily aspirin, and I recommended that my patients over 50 years old do the same. Millions of people took an aspirin every day for years. But it is becoming clear that even solid theory and supporting data are not enough.

The first warnings came from new studies showing that even small doses of aspirin caused more gastrointestinal bleeds than expected. Then, late in 2017, the results of a double-blind long-term study were published. The ARRIVE trial enrolled over 12,000 subjects averaging 55-60 years of age with an average risk for a heart attack; half got aspirin half got placebo. At the end of five years, cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischemic attack had occurred in 4.29% of the aspirin group, and 4.48% of the placebo group.4 The rate of gastrointestinal bleeding was twice as high for the aspirin group. I stopped taking aspirin and decided to write this article.

This will not be the last word on the issue; compliance was inconsistent, and the results may not generalize to people with higher risk. Patients who have had a cardiac event should not stop their aspirin. But the trial offers yet more evidence that there is no substitute for a controlled trial with random assignment…and that clinical recommendations based on apparently solid evolutionary thinking may not be justified, even when apparently supported by data.

  1. Symmers D. The Cause of Sudden Death in Status Lymphaticus. Am J Dis Child. 1917 Dec 1;14(6):463–9.
  2. Adams (Michael) Jacob, Shore RE, Dozier A, Lipshultz SE, Schwartz RG, Constine LS, et al. Thyroid Cancer Risk 40+ Years after Irradiation for an Enlarged Thymus: An Update of the Hempelmann Cohort. Radiat Res. 2010 Dec;174(6):753–62.
  3. Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-Dose Aspirin for the Prevention of Atherothrombosis. N Engl J Med. 2005 Dec 1;353(22):2373–83.
  4. Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. The Lancet. 2018 Sep 22;392(10152):1036–46.
Did natural selection build in adaptive therapy for cancer?

Did natural selection build in adaptive therapy for cancer?

A new article proposes that adaptive therapy for cancer has been there all along as one of the body’s ways of preventing cancer. 

Thomas, F., Donnadieu, E., Charriere, G. M., Jacqueline, C., Tasiemski, A., Pujol, P., … Ujvari, B. (2018). Is adaptive therapy natural? PLOS Biology, 16(10), e2007066. https://doi.org/10.1371/journal.pbio.2007066

Abstract: Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism’s death due to cancer. We propose that organisms’ anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body’s NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body’s NAT and accelerates the evolution of immune resistance.

Cancer transmission via the placenta

Cancer transmission via the placenta

Greaves M, Hughes W. Cancer cell transmission via the placenta. Evolution, Medicine, and Public Health. 2018 Jan 1;2018(1):106–15. (open access

Abstract: Cancer cells have a parasitic propensity in the primary host but their capacity to transit between individuals is severely restrained by two factors: a lack of a route for viable cell transfer and immune recognition in allogeneic, secondary recipients. Several examples of transmissible animal cancers are now recognised. In humans, the only natural route for transmission is via the haemochorial placenta which is permissive for cell traffic. There are three special examples of this occurring in utero: maternal to foetus, intraplacental twin to twin leukaemias and choriocarcinoma-extra-embryonic cells to mother. We discuss the rare circumstances under which such transmission occurs.

Influenza and One Health 100 years after the Epidemic

Influenza and One Health 100 years after the Epidemic

Bailey, E. S., Choi, J. Y., Fieldhouse, J. K., Borkenhagen, L. K., Zemke, J., Zhang, D., & Gray, G. C. (2018). The continual threat of influenza virus infections at the human–animal interface. Evolution, Medicine, and Public Health, 2018(1), 192–198. https://doi.org/10.1093/emph/eoy013

Abstract: This year, in 2018, we mark 100 years since the 1918 influenza pandemic. In the last 100 years, we have expanded our knowledge of public health and increased our ability to detect and prevent influenza; however, we still face challenges resulting from these continually evolving viruses. Today, it is clear that influenza viruses have multiple animal reservoirs (domestic and wild), making infection prevention in humans especially difficult to achieve. With this report, we summarize new knowledge regarding influenza A, B, C and D viruses and their control. We also introduce how a multi-disciplinary One Health approach is necessary to mitigate these threats. 1. Bailey ES, Choi JY, Fieldhouse JK, Borkenhagen LK,