Epigenetics Paper Raises Questions

GENETICS publishes a commentary criticizing a Nature Neuroscience paper claiming that mice can inherit smell sensitivities that their parents acquired during life.

By Kate Yandell | October 16, 2014

WIKIMEDIA, RAMAA commentary published in GENETICS this week (October 15) questions the results of a December 2013 Nature Neuroscience paper about how mice, when conditioned to fear odors, pass on their fears to their pups, as well as to their pups’ offspring, presumably by an epigenetic mechanism. Gregory Francis, the critique’s author and a professor of psychological sciences at Purdue University, suggests that the original paper’s statistical results are “too good to be true.”

Francis has previously written similar statistical reviews of psychology papers. His reviews are based on the theory that experiments, particularly those with relatively small sample sizes, are likely to produce “unsuccessful” findings, such as results that do not reach statistical significance (a p-value of less than 0.05), at least some of the time, even if the experiments are measuring a real phenomenon. Taking into account the researchers’ reports of the strength of the phenomena they are measuring, known as effect size, Francis calculates the probability that an entire series of experiments will be “successful.” In the case of the Nature Neuroscience study, which also showed changes in neuroanatomy and reduced methylation of the body of an odor receptor gene for the sweet-smelling chemical acetophenone in offspring of exposed parents, Francis concluded that there was only a 0.004 chance of getting their pattern of successful results. The researchers either got very lucky, he suggests, or that there was something wrong with their results.

“If the statistical power of a set of experiments is relatively low, then the absence of unsuccessful results implies that something is amiss with data collection, data analysis, or reporting,” he wrote in his GENETICS critique. One explanation could be that the researchers consciously or subconsciously omitted some experiments from the paper, Francis suggested.

Francis said that he submitted his critique to Nature Neuroscience but that “they wouldn’t send it out for review.” Nature senior press officer Neda Afsarmanesh wrote in an e-mail to The Scientist that Nature “cannot discuss specific internal dialog about our papers,” but noted that editors do review all critiques sent to them.

Brian Dias and Kerry Ressler of Emory University, the authors of the Nature Neuroscience paper, responded to Francis’s criticisms in another GENETICS article published this week, stating that they stand by their results and that they have reported all data they collected. They also said that Francis did not mention experiments they included in the supplemental materials that did not yield statistically significant results.

“[Dias] has replicated the main effect that was originally published last year in Nature Neuroscience several times in the lab along with several other people in the lab who have been blinded observers and counters of the data,” Ressler said in an interview. He added that they are working to understand how smell sensitivity might be passed from generation to generation, as it is still unclear how a smell processed in the brain would lead to changes in germ cells.

Gary Churchill, a senior editor of GENETICS and a scientist at The Jackson Laboratory in Bar Harbor, Maine, argued in his own commentary that surprising findings with abundant statistically significant results should be expected to appear in high-profile journals, since authors are more likely submit their most positive results and editors pluck out papers more likely to make splash. Steven Goodman, a professor of medicine at Stanford University and head of a new center for improving the validity of biomedical research, agreed, noting that the improbabilities Francis cites may be as much a result of the peer review and selection process, as they are a result of anything that Dias did.

“Even if Francis is correct that there is a surplus of significance here . . . it doesn’t necessarily invalidate the findings,” Goodman said, “unless he can provide evidence that the effect sizes are implausibly large, that there are internal inconsistencies, that data have been fudged, or that the allegedly omitted experiments are likely to undermine inferences from the experiments presented.”

Others expressed frustration that GENETICS published Francis’s critique. “I’m concerned that the criticism was not based on an apparent experimental error,” said Andy Feinberg, an epigeneticist at Johns Hopkins University. “The danger is that if we allow endless post hoc reanalysis of published work, editors will be even more conservative than they already are in accepting out-of-the-box findings.”

Goodman argues that there are more important factors that should lead people to harbor skepticism toward the Nature Neuroscience paper. For instance, he points out a PubMed Commons comment saying that the paper did not note which mouse pups were siblings in the behavioral and neuroanatomical experiments. Treating related pups as independent from each other can inflate sample sizes.

Dias and Ressler do say that they have made some changes to the way they operate due to statistical criticism. They now track which mice sire which pups, a practice they think more labs should follow. “We just want people to understand that we’re very devoted to finding the truth and to [being] as transparent with the data as we can,” Ressler said.

G. Francis, “Too much success for recent groundbreaking epigenetic experiments,” GENETICS, 198:449-51, 2014.

B.G. Dias and K.J. Ressler, “Reply to Gregory Francis,” GENETICS, 198:453, 2014.

G.A. Churchill, “When are results too good to be true,” GENETICS, 198:447-8, 2014.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 532

October 16, 2014

"Scepticism that the inheritance mechanism is real will likely persist, Ressler says, “until someone can really explain it in a molecular way”, says Ressler. “Unfortunately, it’s probably going to be complicated and it’s probably going to take a while.

Evolutionary theorists may never accept an explanation that links biophysically constrained conserved molecular mechanisms and the chemistry of protein folding to morphological and behavioral phenotypes across all genera. Like evolutionary theists, theorists have accepted a theory about mutations and natural selection and never examined what must occur in the context of ecological variation and nutrient-dependent ecological adaptations.

For comparison, serious scientists have continued to link RNA-directed DNA methylation and cell type differentiation via RNA-mediated events and amino acid substitutions that differentiate all cell types in all individuals of all living species. The fact that the amino acid substitutions also differentiate influenza strains via single amino acid substitutions and Ebola viruses continues to be ignored by theorists and science journalists.

For example, Carl Zimmer, does not seem to know any serious scientists, although the link from the RNA world of viruses to the RNA-mediated world of cell type diffentiation in living organisms was make clear by Villarreal in the context of nutrient-dependent pheromone-controlled ecological adaptations.

It has become clear that pheromone-controlled nutrient-dependent ecological adaptations eliminate theories about mutations and natural selection from consideration in the context of RNA-mediated events and amino acid substitutions that Dobzhansky (1973) reported in the following context: "...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla."

Now that other serious scientists are aware that a single amino acid substitution makes a huge difference in species from non-living viruses to primates, the problem that theorists and evolutionary theists have with accepting biologically-based facts has become clear.  Dobzhansky (1973) also reported:  "I am a creationist and an evolutionist."

RNA-mediated events that lead to the differentiation of cell types via amino acid substitutions link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via conserved molecular mechanisms. Explaining their results in a molecular way, as Ressler indicates is required, eliminates evolutionary theory from any further consideration whatsoever. It has been replaced by what is currently known about the physics, chemistry, and molecular biology of RNA-mediated amino acid substitutions and biodiversity.

Results of experiments that can be integrated across disciplines may be "...too good to be true..." for evolutionary theorists and evolutionary theists because they support another claim made in Dobzhansky (1964).  "... the only worthwhile biology is molecular biology. All else is "bird watching" or "butterfly collecting." Bird watching and butterfly collecting are occupations manifestly unworthy of serious scientists!"

Avatar of: Cthulhu


Posts: 1

Replied to a comment from James V. Kohl made on October 16, 2014

October 16, 2014

Ad hominem attacks do nothing to bolster arguments for a field that appears to lack evidence for its most basic assumptions. When epigeneticists can substantiate their claims and conclusions via the scientific method, their research and results will be taken seriously. 

Avatar of: James V. Kohl

James V. Kohl

Posts: 532

Replied to a comment from Cthulhu made on October 16, 2014

October 16, 2014

Thanks. How many more examples do you think are required to substantiate the claims and conclusions of epigeneticists?

Elekonich and Robinson (2000) extended our yeasts to mammals model of RNA-mediated events to insects in Organizational and activational effects of hormones on insect behavior. Elekonich and Roberts (2005) extended it to life history transitions in the honeybee model organism in Honey bees as a model for understanding mechanisms of life history transitions.

Are you claiming there is not enough experimental evidence to link what we reported about RNA-mediated events in From Fertilization to Adult Sexual Behavior via the conserved molecular mechnaisms of cell type differentiation now exemplified in many more species? If there is not enough experimental evidence to link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man via RNA-mediated events, why do you think no one has proposed a model in response to my request in my most recent published review?

"...the model represented here is consistent with what is known about the epigenetic effects of ecologically important nutrients and pheromones on the adaptively evolved behavior of species from microbes to man. Minimally, this model can be compared to any other factual representations of epigenesis and epistasis for determination of the best scientific ‘fit’.'

See also: Arrival of the Fittest: Solving Evolution's Greatest Puzzle

I think the problem is the lack of experimental evidence of biophysically-constrained biologically plausible cause and effect that might support the claims of evolutionary theorists and evolutionary theists.

What made them think their theories would not be replaced when experimental evidence showed how ridiculous the theories have continued to be while framed in the context of mutations, natural selection, or the evolution of biodiversity, which is obviously nutrient-dependent and pheromone-controlled?

What kind of null hypothesis is reported by people like Zimmer, as "Others maintain that as random mutations arise, complexity emerges as a side effect, even without natural selection to help it along. Complexity, they say, is not purely the result of millions of years of fine-tuning through natural selection—the process that Richard Dawkins famously dubbed “the blind watchmaker.” To some extent, it just happens."

If the Ebola viruses adapt via amino acid substitutions that stabilize their protein folding fast enough to eliminate most humans who cannot ecologically adapt as quickly due to our organismal complexity, will theorists simply claim that  our species extinction is about to "just happen" ?

Avatar of: James V. Kohl

James V. Kohl

Posts: 532

Replied to a comment from James V. Kohl made on October 16, 2014

October 17, 2014

"But the reviewers of Physical Review Letters and the Journal of Statistical Physics refused to publish my texts: they contained too innovative ideas."

Similarly, reviewers refused to review my invited submission on nutritional epigenetics. When I submitted it to another journal, the editor rejected it because he did not want to be involved in any controvery about evolutionary theory.

What controversy?

See:  Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems 

or the 5.5 minute long video representation of RNA-mediated events.

Is there any aspect of evolutionary theory that links atoms to ecosystems via conserved molecular mechanisms of cell type differentiation? Is it past time for theorists and evolutionary theists to describe biologically-based evolutionary events or quit telling people we evolved and admit that -- like all other species -- we ecologically adapted to ecological variation?

Avatar of: Roy Niles

Roy Niles

Posts: 116

Replied to a comment from James V. Kohl made on October 17, 2014

October 20, 2014

The last thing we need is to have Kohl supporting epigenetics with his own phony version of how it works.  Epigentics works as an intelligent process of evolution rather than a stochastic process.  The organism evolves itself through a complex system of optional trials, necessary errors, analysis of mistakes, retrials, provisional acceptance of progressive results.  Yes, all biological systems have a version of intelligence, the ability to acquire and apply knowledge and skills.  Nothing could have "accidentally" evolved without it.  For more info. from real scientists, read the ground breaking works of James A Shapiro or of Mae-Wan Ho.

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