Evolution meets evidence-based medicine


This is the EvolutionMedicine ‘cast #4, a bonus podcast for Saturday July 23th – evolution meets evidence-based medicine. This podcast is based on a presentation I gave at last month’s ISEMPH conference. A couple of weeks ago, we discussed how an evolutionary hypothesis regarding sepsis physiology was ultimately vindicated by evidence.  Xigris’ demise was the culmination of over 1000 publications, but a final well designed randomized controlled trial was the final nail in Xigris’ coffin.

Xigris’ failure was an example of the evidence-based medicine (EBM) dovetailing with predictions of evolutionary medicine. EBM is a movement in medical science that makes receommendations based on the best evidence provided by clinical trials. The hierarchy of EBM is shown here:

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Randomized controlled trials are the best quality evidence, especially when synthesized into systematic reviews.

If evolutionary medicine (EvMed) is a useful enterprise that produces better patient outcomes, then EBM and EvMed should overlap more often than not. Lets see if this proposition holds up, starting with evidenced-based opioid pain medication prescribing.

Here is our question: Should I prescribe an opioid pain medicine for patients with chronic musculoskeletal back pain?

Listen to the podcast:

Slides for this talk are available here

 

 

 

The New Normal – Podcast #3

This is the EvolutionMedicine ‘cast #3, entitled The New Normal, for Wednesday July 13th.

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Over half of all medical interventions are harmful or ineffective. Source: Clinical Evidence, BMJ.

This podcast is based on a presentation I gave at last year’s ISEMPH 2015 conference. I actually recorded this audio two weeks ago. That is why it is mis-identified  as podcast #1. It is indeed ‘cast #3! Careful listeners will also notice that this episode also mentions the need to cover Xigris in detail, and of course Xigris was the topic of last week’s podcast. Please forgive my lack of editing skills, which will come in time! But today is a good time to cover whether evolution can inform the question: “when to intervene, and when to leave alone.”

Enjoy:

More on Euboxia, a well-described physician bias favoring normal results, here.

 

 

The evolutionary lesson of Xigris

This is the EvolutionMedicine ‘cast #2, for July 4, 2016. This is a story worth telling.

Sepsis is an important cause of mortality, causing an estimated 60,000 deaths yearly. Sepsis is also expensive to treat, and is associated with expensive medical procedures, such as life support and intensive care. Despite advances in supportive care over the last 30 years, the mortality rates have remained stubbornly high, as much as 30-40%.

Sepsis MortalityPersistently high sepsis mortality prompted many researchers and funding organizations to seek anti-inflammatory treatment to decrease the apparently harmful immune effects of sepsis, which has been described as an out of control inflammatory response.

One thing that biomedical researchers noticed was that septic patients who die often had low levels of activated protein C.  A recombinant form of activated protein C, called  Xigris, has anti-inflammatory and anticoagulant properties. Since inflammation was thought to be out of control in the systemic inflammatory immune response, it stood to reason that an inhibitor of inflammation and clotting might reduce deaths in sepsis.

In 2001 the PROWESS study appeared to show just that.

10 years late, on October 25, 2011 the FDA recommended that Xigris be withdrawn from the market. Remarkably, the company selling Xigris, Eli Lilly, was able to profit from this ineffective drug for nearly the entirety of the time Xigris was under patent. The long road to arrive at this conclusion is an interesting story.

What if the immune and coagulation responses are adaptive in septic shock? If so, anti-clotting/inflammation treatments, like Xigris, will fail. Supporting that notion is the recent experimental experience with recombinant activated protein C:

Epitaph for Xigris – I never worked a day in my life!

What lesson from Xigris’s failure can we learn about the functioning of the immune system, about sepsis, and evolution? Notably, Xigris is not the only high-profile failure for sepsis immunomodulatory therapy. A more recent anti-inflammatory therapy, a toll-like receptor TLR-4 blocker known as Eritoran, also failed spectacularly in clinical trials.

Not be deterred, a new therapy for sepsis targeting the pro-inflammatory cytokine TNF-alpha, based on a compound called CytoFab, was recently tested. How do you suppose that one went? Shockingly, it too failed.

Why have clinical trials in sepsis failed?

Table 1 showing failed clinical trials of immune and other therapies in sepsis above, and the abstract below, is reproduced from Marshall Why have clinical trials in sepsis failed? Trends Mol Med 2014

“The systemic inflammatory response is biologically complex, redundant, and activated by both infectious and noninfectious triggers. Its manipulation can cause both benefit and harm. More than 100 randomized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival. With one short-lived exception, none of these has resulted in new treatments. The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate large studies of clinical and biochemical epidemiology to understand the course of illness, better integration of basic and clinical science, and the creation of stratification systems to target treatment towards those who are most likely to benefit.”

These examples suggest that continuing to search for elusive so-called “magic bullets” in sepsis is a losing strategy. As cited in a recent article about the failure of anti-TNF-α in sepsis:  “Success is the ability to go from one failure to another with no loss of enthusiasm,” a quotation attributed to Sir Winston Churchill. On the other hand, repeating same thing while expecting different results is also…well you know the cliché. Japanese investigators are at it again with a medication, ART-123, that works along similar lines at Xigris, at an earlier stage in the pathway leading to activated protein C. I predict the same fate for ART-123 as Xigris.

Hemostatic containment article is here

My previous post on why blood clotting is host defense and why bacteria dissolve clots

10 evolutionary mistakes physicians make

My post on underlying assumptions of sepsis treatment

Additional references from the podcast are in this file: Xigris epitaph

© Joe Alcock MD

EvolutionMedicine: the podcast

 

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Joe Alcock MD – Welcome to the new EvolutionMedicine podcast

I am launching a new podcast in evolutionary medicine. It will be available here at EvolutionMedicine.com for now. We plan to have this podcast on iTunes and other platforms, but not yet! Here is the inaugural EvolutionMedicine ‘cast: The State of the Science of Evolutionary Medicine. Many more to come.

Venn Diagram

Evolutionary Medicine includes these three domains

Note: I mentioned Nescent in the podcast. It is now TriCEM. Check it out: Tricem.org

Follow this link for the International Society for Evolution Medicine and Public Health nudge, nudge,  you should sign up!

The Evolution Medicine and Public Health journal is here: emph.oxfordjournals.org good stuff!

The Arizona State University’s Center for Evolution and Medicine is here: Evmed.asu.edu

EvMedEd is a great resource: EvMedEd.org

The Emergence of Evolutionary Medicine, Journal of Evolutionary Medicine

 

 

 

International Society for Evolution Medicine & Public Health

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the author (second from left) and friends

The 2016 ISEMPH meeting held in Durham, North Carolina, just finished up today. We had over 250 attendees from a dozen countries (at least) and great representation by physicians, nurses, evolutionary biologists, anthropologists, evolutionary psychologists, historians, science writers, residents, and graduate students. I was happy to see old friends and make a bunch of new ones. Next year we will hold the annual meeting in Groningen, Netherlands August 18-20, 2017.

If you missed this year’s conference, many of us wrote brief summaries of all the sessions from the meeting. All the summaries of the sessions are available at the Evolution and Medicine Review.  Links will take you to descriptions of plenary lectures by Josh Schiffman, Marty Blaser, and Helen Ball. I will post more individual links of the plenaries here when I get them.

© Joe Alcock MD

The friendly microbiome (or not)

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The Greek god Janus

Recent discoveries have highlighted the importance of the human microbiome to human health in 1) shaping normal gastrointestinal and immune development, 2) regulation of healthy body weight, 3) prevention of gut and other infections, 4) providing necessary vitamins, 5) influencing mood and normal brain function. These insights have led some researchers to propose that the human microbiota is a forgotten organ, as complex and integrated into the healthy functioning of our bodies as our own organs. For instance, the collective metabolism of microbes in our guts is equivalent to the metabolism carried out by the liver. The microbiota also generates hormones and neurochemicals, with body-wide effects and so might be considered an endocrine organ. However, this microbial organ is unique in containing multitudes of distinct genomes, each with competing genetic interests and potential for conflict. Because of this difference, the microbiome is an organ like no other.

One way the microbiome is a different kind of organ is illustrated by germ free animals. Experimenters are able to raise germ-free animals in a microbe free facility. And, they don’t drop dead (the animals, not the experimenters)! In fact, germ free animals have been reported to live longer than their conventional counterparts. This is true for rats, and in fruit flies, (but perhaps not always)

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Credit: Edan Foley

The only other organs that can be removed thereby increasing longevity are the reproductive organs, but that has a pretty big negative effect on fitness.

The other feature of the microbiome is its potential to turn on you if conditions get bad. Under stress, previously benign bacteria transform into deadly pathogens. This is particularly true of microbes with pathogenic potential, like Pseudomonas and other gram negative bacteria. But even nonpathogens become invasive if given the chance. Finally, microbes from the microbiome immediately disseminate throughout your body after you die, highlighting the fact that the body must expend much effort to corral the microbiome to the reservoirs where it is tolerated.

The Jekyll and Hyde nature of the microbiome explains a variety of phenomena that are otherwise hard to fathom. First, it may explain why the body responds so differently to different foods, for instance to different kinds of fat with the same calorie content. It may also explain why gene expression in humans appears to be exquisitely sensitive to the composition of the microbiota in the gut. It can be inferred that the composition of the microbiota, and the behaviors and functions of the microbiota, have had a profound fitness impact on their hosts during the evolution of life on this planet. Because these impacts are good and bad, our bodies often respond in radically different ways to different microbes, and in opposite ways to nutrients that shape the microbiota.

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The table above, from (Alcock and Lin 2015) shows the diverging effects of various fats on insulin resistance (a prediabetic state) and inflammation. These differences only make sense if the microbiome is not uniformly mutualistic, instead varying along a mutualism-parasitism continuum.

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A more realistic view of the microbiome is illustrated above (credit: C. Maley). The fitness impacts of the microbiota range on a spectrum of parastitism (conflict) to mutualism (cooperation). The host is highly sensitive to changes in the microbiome and often responds in a way that compensates for these changes. The combination of host response and microbiome behavior can either lead to health or disease, depending in large part on whether the fitness interests of host and microbiome are aligned or not.

As we described in a recent post, whether cooperative behaviors or conflict exists between human host and microbome often depends on what we eat.

Read our recent paper here: Wasielewski H, Alcock J, Aktipis A.Resource conflict and cooperation between human host and gut microbiota: Implications for nutrition and health. Annals of the New York Academy of Sciences. June 6 2016 

Also:

Alcock J. Lin H.C., Fatty acids from diet and microbiota regulate energy metabolism. F1000 Research. September 2015.

 

Copyright © Joe Alcock MD

Olfaction as microbiome detection

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A recent study showed that germ free mice have altered olfactory epithelial development and function. This makes sense if one of the functions of olfaction is to detect and direct responses to the microbiome.

(Alternatively, advocates of the super-organism concept of microbiome-host evolution might view this as microbes assisting the host to direct normal olfactory development.)

The authors suggest that this mechanism might be one way that the composition of the microbiota may influence eating behavior, since olfaction is important in eating.

The article  by François et al in Scientific Reports (2016) is here: Olfactory epithelium changes in germfree mice

A few years ago, this blog highlighted a related article, entitled “Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation” Jennifer Pluznick in PNAS (2012) describes how short chain fatty acids – produced by gut microbiota – are detected by olfactory receptors in blood vessels. These olfactory receptors have the effect of regulating blood pressure!

From the abstract:

Olfactory receptors are G protein-coupled receptors that mediate olfactory chemosensation and serve as chemosensors in other tissues. We find that Olfr78, an olfactory receptor expressed in the kidney, responds to short chain fatty acids (SCFAs). Olfr78 is expressed in the renal juxtaglomerular apparatus, where it mediates renin secretion in response to SCFAs. In addition, both Olfr78 and G protein-coupled receptor 41 (Gpr41), another SCFA receptor, are expressed in smooth muscle cells of small resistance vessels. Propionate, a SCFA shown to induce vasodilation ex vivo, produces an acute hypotensive response in wild-type mice. This effect is differentially modulated by disruption of Olfr78 and Gpr41 expression. SCFAs are end products of fermentation by the gut microbiota and are absorbed into the circulation. Antibiotic treatment reduces the biomass of the gut microbiota and elevates blood pressure in Olfr78 knockout mice. We conclude that SCFAs produced by the gut microbiota modulate blood pressure via Olfr78 and Gpr41.

The article published in 2012in PNAS is available here: Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation

Addendum: We should not be too surprised that olfactory receptors are linked with microbe detection and the immune system. Read this article by Pacheco-Lopez and Bermudez-Rattoni for more on the adaptive role of olfaction in detecting microbes, protecting against infection, and modulating human behavior.