The new Op-Ed feature started last month with a piece by Joe Alcock, “Disabling the smoke detector in sepsis.” Our hope was that this feature would spark interest and contributions by more authors and so far we are off to a great start. Veterinary pathologist Edmund LeGrand has volunteered the following piece which examines, from an adaptationist viewpoint, the intriguing question as to why the human heart has such limited powers of post-infarction regeneration. We’d like to thank both Ed and Joe for their contributions and remind readers that we are open to contributions from anyone. We also want to encourage commentary on all of our Op-Ed pieces; please feel free to submit contributions and comments for approval to editor@evmedreview.com.

Regeneration and the Heart of the Adaptationist Approach

Edmund K. LeGrand, DVM, PhD, DACVP

The ability to regrow an arm, a leg, or another large portion of the body that has been amputated is a more widespread trait than you might think. Invertebrates like sea stars and flatworms can replace most of their body parts after removal, but even some vertebrates have impressive regenerative abilities. Lizards regenerate their tails, newts can regrow limbs and repair parts of the eye, and zebrafish can regrow fins and repair other tissues like the heart. Mammals, however, are pretty limited in this realm of regrowth. Humans can regrow muscle and liver tissue, but regenerative repair of other organs, including the heart, is extremely limited. Why might this be? Two recent papers are notable in addressing the question (1, 2).

The review paper “Evolution, comparative biology and ontogeny of vertebrate heart regeneration” (1) provides an in-depth comparative analysis of factors correlated with heart regeneration. Either phylogenetically or developmentally, myocardial regeneration seems to be associated with “a low metabolic state, low heart pressure, immature cardiomyocyte structure, hypoxia, an immature immune system and the inability to regulate body temperature.” It was considered that there may be limiting trade-offs involving some of these factors.

Trade-offs may be the second favorite word, after selection, of those who take the adaptationist approach of asking “why” or “why not” questions.  Given that stem cells can replenish most tissues (there are even small numbers of myocardial stem cells in adult humans (3)) and that ancestral organisms and embryos have myocardial regeneration, the question seems to go beyond “Why can’t the adult human heart repair itself?” Rather, we might ask “Why doesn’t the heart repair itself?” and “What problems might arise were regeneration to occur?”

Sometimes finding a possible answer requires looking at a problem from a new vantage point. A number of years ago while addressing the apoptotic propensity of various cell types, it struck me that neurons and cardiomyocytes, with low replacement rates and hence a disinclination to undergo apoptosis, have life-long interactions with neighboring cells (4). As with a world-class sports team or symphony involving high levels of skill and precise interactions, each team member adapts to the others’ strengths and compensates for their weaknesses through long-term association. For the brain and heart, an important question becomes “Under what conditions should dead cells be replaced or not?” Each neuron is highly specialized; the same can’t be said for cardiomyocytes, which have two main roles requiring precision: to contract and to conduct the electrical rhythm to neighboring cells. I suggested that “perhaps in the short period of time when a newly created replacement cell is establishing contacts (gap junctions) with its new neighbors, there might be enough disruption of electrical impulse conduction to start an arrhythmia.”

Itachycardia-image2n the October 20, 2016 issue of Nature, Shiba et al (2) advanced the long-sought goal of injecting myocardial stem cells into heart tissue to help repair infarcts in monkeys. Notably, four of five monkeys with an infarct treated with injected myocardial stem cells developed sustained ventricular tachycardia (though the monkeys were asymptomatic) versus none of the five placebo-treated controls. Thus, it is possible, though not confirmed, this could be a trade-off that reduces the benefit of heart regeneration.  While the authors emphasized the success of injected stem cells in integrating and coupling with surviving cardiomyocytes, they concluded by saying that “further research to control post-transplant arrhythmias is necessary.”

Having spent a career as a comparative pathologist in the pharmaceutical industry, I appreciated Joe Alcock’s recent op-ed in The Evolution and Medicine Review (Oct. 9, 2016) noting the repeated failures in developing treatments for sepsis. My frustrations with the absence of adaptationist thinking in drug development had previously led me to address the issue (4,5). I stated that the scientific community will soon know what each gene product does, making possible the creation of drugs that can affect each protein. But that mechanistic understanding doesn’t guarantee that the evolutionary function will be understood. Without taking the adaptationist approach, the full understanding of the phenomenon may not be achieved until problems arise in preclinical development in animal models, in clinical trials, or (more disastrously) after the product is on the market.

In approaching why myocardial regeneration is limited in mammals, it’s important that we listen for those smoke detector alarms. Luckily, the problem of arrhythmias with myocardial regeneration was discovered early in the therapeutic development process. While it wasn’t obvious what the trade-offs are in myocardial regeneration, it was certainly clear that trade-offs are involved. In many areas of medical research, a more thorough approach that emphasizes asking the whys can help us avoid unnecessary clinical missteps and can help us get to the heart of a problem.

References

  1. Vivien, CJ, Hudson JE, Porrello ER. 2016. Evolution, comparative biology and ontogeny of vertebrate heart regeneration. npj Regenerative Medicine 1:16012.
  2. Shiba Y, et al. 2016. Allogenic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 538:388-391.
  3. Urbanek K, et al. 2005. Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proceedings of the National Academy of Sciences 102: 8692-8697.
  4. LeGrand EK. 1997. An adaptationist view of apoptosis. Quarterly Review of Biology 72: 135-147.
  5. LeGrand EK. 2001. Evolutionary thinking as a tool in pharmaceutical development. Drug Development Research 52:439-445.

Image showing ventricular tachycardia via TextbookofCardiology.org, by user Drj.