Peter Rodgers Reviewing Editor; eLife, United Kingdom In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.

Thank you for submitting your manuscript "Neurobiology of Homo sapiens: what went wrong?" to eLife for consideration as a Feature Article. Your manuscript has been reviewed by three peer reviewers, and the evaluation has been overseen Peter Rodgers as the eLife Features Editor.

The full reports from the reviewers are below. The following individuals involved in review of your manuscript have agreed to reveal their identity: Jeremy Gunawardena (Reviewer #2) and Bruce McEwen (Reviewer #3).

While the reviewers found the manuscript to be interesting and provocative, they also found it to be "speculative and superficial" in places. It is vital, therefore, that you fully address all the concerns of the reviewers in a revised version of the manuscript. In particular, you need to address the following points:

– Referee 1. Point 1 (which argues against the conclusion that "modern life shrinks reward diversity.")

– Referee 1. Point 2 (which argues against the conclusion that something has "gone wrong"/that we face a "crisis"). Referee 2 makes a similar point in paragraph 7 of his report.

– Referee 2. The comments in paragraph 4 (about extreme teleological language).

– Referee 2. The comments in paragraph 8 (about language and culture).

– Referee 2. The comments in paragraph 9.

– Referee 3. The comments in paragraph 2 (about the role of the human prefrontal cortex)

Reviewer #1:

This article discusses the origin of various "crises" impacting the human race (climate change, obesity) and argues that they all originate from the drive for positive reward prediction error, which in a society of abundance results in excessive consumption. The article is interesting and provocative in a popular science way, and presents many intriguing connections between evolution, neuroscience, history, and behavior that will stimulate thought among readers. But it is also extremely speculative and superficial in its treatment of these topics.

Major points

1) This is a strange article in that it is extremely broad, speculating about everything from the evolution of life on earth to the modern opioid epidemic. I am not sure that something like this belongs in a scientific journal that publishes original research such as eLife, or at least I am not sure by what criteria it should be reviewed. The article skips through so many different areas of biology at such a superficial level that it is unclear where to begin with criticism. For example, a central conclusion is that "modern life shrinks reward diversity." Is this true? I could make a counterargument that life as a hunter-gatherer was likely repetitive, and that my modern existence as a scientist living in San Francisco provides a much greater diversity of interesting and unexpected stimuli. But in any case the author provides no evidence for his position beyond examples and anecdotes.

2) The article starts from the premise that something has "gone wrong" with the human race and that we face a "crisis". But by virtually every measure the human race is better off now than it has been at any point in history – longer lifespans, better health, greater freedom and security, etc. The "crisis" that the author describes consists of a few cherry-picked examples that support his thesis. It is reasonable to suggest that obesity or drug addiction may be caused by dysregulated reward systems, but the author instead wants to propose an overarching theory for life on earth.

Reviewer #2:

1) This is a fascinating and ambitious paper, which contains many interesting ideas that should be of broad interest. However, it also contains suggestions that are poorly worked out, which get in the way of appreciating the former.

2) The author attempts something that is increasingly rare, which is to integrate our scientific understanding across the scales from the molecular to the physiological to the social. I can think of few other scientists with the chutzpah to attempt this, with the exception perhaps of Jean-Pierre Changeux ("Climbing brain levels of organisation from genes to consciousness", TICS 21:168-181 2017). This kind of integration is sorely needed, because the rest of us are too scared to attempt it, and I vigorously applaud the author for trying.

3) The most interesting and most important ideas centre around "allostasis", or the re-evaluation of the classical homeostasis of Claude Bernard and Walter Cannon to incorporate the central nervous system, prediction, motivation and feed-forward regulation (Figures 3 and 11). This draws on the author's own seminal contributions (Sterling, 2012), as well as the powerful synthesis of neural "design principles" in the author's collaboration with Simon Laughlin (Principles of Neural Design, MIT Press 2015). These ideas suggest that the organism is not just responding to its environment, as in classical homeostasis, but actively, if largely unconsciously, exploring and internalising it. The organism acquires thereby an unconscious autonomy over aspects of its functioning that has previously been overlooked (Figures 10 and 12). This is an extremely provocative viewpoint and I quite understand why the author feels it ought to have profound implications for how we think about the human organism in the context of upbringing, education, illness and participation in society.

4) Allostasis is described within an account of how increasing information-processing complexity has emerged from the first primordial cells to us (first 3 sections after the Introduction). This would be engaging and entertaining were it not for its extreme teleological language. For example, "Cells began to accumulate odd sequences that could serve some future challenge", "Moreover, an animal could specialize many cells for rapid signaling and thus greatly expand its channels for processing information". What?! Evolution could look ahead, could it, to see what it would need in the future? It will be anticipating the emergence of humans next. Who needs intelligent design when a biologist writes like this? Of course, the author knows better, which only makes it worse. Evolutionary biologists must despair of the rest of us.

5) The clinical context is where allostasis should have the most traction, by providing an alternative to traditional pharmacology's "magic bullet", as trenchantly described in "Treating the lowest levels". Working out a strategy for reaching the "higher levels" and convincing clinicians of its value would be an immense contribution.

6) However, the paper does not take this route. It seeks instead to stretch much further and here the ice starts to crack, if not disappear altogether. According to the author, the human species "went wrong" by discovering capitalism (Figure 8), which "shrank reward diversity" (Figure 9), so that our allostatic biology led inexorably to global warming and a pandemic of ignorance, stupidity, Big Macs, obesity, diabetes, hypertension and addiction. Furthermore, we are all so different that mental disease should be placed on a continuum, rather than treated categorically ("Understanding human differences"). I do not find these assertions compelling for many reasons.

7) First, each of them is worthy of a paper, if not a book, in its own right, which, to be credible, would have to take on board a formidable body of existing literature. In the case of what "went wrong", if, in fact, anything did, the discussion would have to go back at least as far as Rousseau's "noble savage". As they stand, these assertions come across as the author's personal view of the World.

8) Second, there is a long, and mostly unhappy, history of biologists trying to contribute to the human sciences. The author is attempting to do this at a very ambitious level but there is a striking failure to mention the key concepts which differentiate us from other animals and which form the intellectual currency of the humanities – language and culture. Allostatic biology is shared with many other animals. Language and culture are not. The former appears once in the paper, as an example of brain specialisation, and the latter appears not at all. How can they not be part of the explanation? Sociobiology at least attempted to say something about culture, with the "gene" as the unit of explanation, however unwelcome that was to most social scientists, but the author ignores culture, as if to say that allostatic "design", in place of "gene", is now sufficient to explain human behaviours and societies. There is an enormous gaping chasm here, to put it mildly.

9) Finally, these assertions lead to suggestions of what we should do to "resolve the tension between our biology and how we now contrive to live", which are, as listed in the "Conclusions", to "develop constructive niches for individuals", "reverse the trend toward becoming ever more stupid and ignorant", "identify each child's special gifts", "renew sacred practices" and be accommodating of sociopaths. I am afraid these strike me as platitudes.

10) In summary, there is an important and interesting paper here but it needs sharper focus and ruthless editing to extricate it from the author's personal beliefs. The updated view of the organism that the author is putting forward is worthy of serious scientific attention. If it becomes broadly influential, as it should, then perhaps in time it may help lead to the changes in society that the author wants to see. If so, it will be others who accomplish such change, not the author. He does himself, and us, a disservice by seeking a final cause, rather than allowing evolution to take its course.

Reviewer #3:

1) Thoughtful, informative of the science, and enjoyable to read. Clearly the author is very passionate about this topic and rightly so!

2) One possible addition, to what is implied but not stated, is to add a discussion of the variable role of the human prefrontal cortex in self-regulation of impulses, mood and other behaviors as well as proactive planning. The PFC develops after birth in formative years of childhood, adolescence and into young adulthood, and it develops more quickly on the average in females. (Hence, why for young males, auto insurance rates are higher than for females!) The variability of results of the famous "marshmallow test" on children indicates how variable among individuals is "self-regulation"; tests on children turn out to be predictive of self-regulations 40 years later! Early life adversity redirects the PFC development and is likely to be a contributor to the variability in impulsiveness, quarrelsomeness, proactive planning (e.g. for the future of our planet) as well as the pursuit of consumption and hedonic rewards.

3) Clearly education is an important factor. Our prolonged developmental period as humans allows the fortunate to develop the perspective needed to do what the author advocates. So many people are not so lucky!

[Editors' note: further revisions were requested prior to acceptance, as described below.]

Thank you for submitting the revised version of your article "Predictive regulation and human design" to eLife. I have received comments on the revised version of article from two of the reviewers who reviewed the original version, and discussed the revised version and these comments with another editor.

We agreed that you need to address some of the points made by Jeremy Gunawardena, and that we will accept the article for publication if you address these points plus a number of editorial points.

Re the comments from Jeremy Gunawardena: Please address the following points:

– point 3

– points 4 and 5 (which are related)

– points 6 and 7 (which are related)

– point 8. (Addressing some of the editorial comments should help address this point)

1) The author has made substantial changes to the original draft but not really in the way I was hoping for. Some of the interesting scientific details have been lost (previous Figures 5, 6, 10, for instance) but the personal opinions largely remain. However, the changes have made the logic of the argument clearer and I will focus on that.

2) To summarise, the author's claim is that the dopamine-based, reinforcement learning system which we share with other animals entered a regime of "positive feedback" in which "consumption grows explosively" because "modern life shrinks reward diversity", and this led to our "present difficulties" of "climate change, obesity, drug addiction".

3) Like reviewer 1, I am not convinced that modern life has lower reward diversity than that of an agricultural labourer in 1700 CE or a stone carrier undertaking the "monumental construction" of the pyramid of Cheops in ~2500 BCE. I expect it is quite the reverse. The author does not tell us how reward diversity can be measured and the issue tested, so this remains a matter of opinion. That is part of the problem, especially when personal opinion is not clearly stated as such (see point 8).

4) Even if we give the author the benefit of the doubt over point 3, I do not understand the claim that reinforcement learning systems lead to positive feedback and explosive growth. As the author points out, these learning algorithms have properties of optimality within a specified mathematical context (Niv, J Math Psych, 53:139-54 2009). Positive feedback and explosive growth are pathologies, which would destroy optimality. So, how do they arise?

5) The author suggests that they do so through habituation: "all neurons and circuits adapt. As a result repeats and becomes predictable, its targets at the molecular and circuit levels reduce their sensitivity". That is well and good but habituation leads to levelling off, not positive feedback, and levelling off is what a reinforcement learning system would do if it kept receiving the same reward. No instability arises. The assertion that reinforcement learning systems become pathological is not justified.

6) It is an enormous leap to implicate dopamine reward pathology as the cause of our present crises (I have no problem calling them that). I previously pointed out that culture is the more conventional culprit. I did not mean by culture, "art, music, etc.", but rather the societal infrastructure – language, laws, Government, economy, industry, media, institutions – which has allowed us to dominate the planet. The author has not convinced me that biology is a better explanation for the crises than culture, understood in this sense.

7) To clarify the difficulty, let us consider drug addiction because this is an area in which dopamine-based reward systems may play an important role in individual pathology (Berridge, Psychopharmacology, 191:391-431 2007). But is the reward system the cause of the addiction crisis? During the Opium Wars of the 19th century, the British East India Company used gunboat diplomacy to force the Chinese Qing dynasty to license opium sales in China, resulting in an addiction crisis that affected a large part (some reports suggest 25%) of the population. Was the crisis due to an "explosive" dopamine system in the Chinese or to the British creating the world's first drug cartel? I think the latter is "the cause" and I suspect most commentators would do the same. This is not to say that the biology is unimportant but it seems more plausible that its role is in deciding who becomes addicted, and who escapes, rather than being the root of the crisis, which lies in culture and society (here, British imperialist trade policy).

8) As I said previously, the author has put forward some fascinating and important scientific ideas that deserve wider attention but I fear these are getting lost in the speculation and personal opinion. This is a perspective, of course, and speculation and personal opinions can sometimes be hugely beneficial in stimulating fresh thinking. I have no problem with that but speculation needs to be clearly seen as such and not dressed up as if it were science. The author states in his rebuttal letter that he has recast his views as a hypothesis and seems to feel that his personal opinions have been adequately segregated. I do not agree. I think these are still very much present in the issues discussed above. The main claim is more clearly a "hypothesis" in the rebuttal than in the revision. In the latter, "hypothesis" is used directly only to refer to "alternatives" and only once used, indirectly, to refer to the "present hypothesis". The speculative nature of what is being claimed and the extent to which it reflects personal opinion is not adequately stated in the new draft.